CH648300A5 - Phenanthrene derivatives and medicaments containing them - Google Patents

Abstract

The 4,5,5a,6-tetrahydro-5-dibenz[cd, f]indoles contain at least one hydroxyl substituent in one or both of the condensed benzene rings, one at least of the hydroxyl substituents being a hydroxyl or alcyloxy group when the molecule is unsubstituted in position 4. These compounds can be used therapeutically as active principles in medicaments.

Description

       

  
 

** ATTENTION ** start of the DESC field may contain end of CLMS **. 

 
EMI2. 1
 in which
 the symbols Z each represent an arylalkoxy or alkoxy group containing up to 10 carbon atoms,
   R'l represents a hydrogen atom, and
 R2 represents an alkyl group containing from 1 to 5 carbon atoms. 



   17.    4,5,5a, 6-Tetrahydrodibenz [cd, faindole according to one of claims 13 to 16, characterized in that the ether group is a methoxy group. 



   18.    4,5,5a, 6-Tetrahydrodibenz [cd, flindole according to one of claims 1 to 17, characterized in that it is in the form of an optically active isomer. 



   19.  A 4,5,5a, 6-tetrahydrodibenz [cd, ffindole according to claim 1, characterized in that it is chosen from (+) - (4R, SaS) - 4,5,5a, 6-tetrahydro-9 , 1 0-dihydroxy-4,5-dimethyldibenz [cd, fzindole, le (-) - (4S, 5aR) -4,5,5a, 6-tétrahydro-9, 1 0-dihydroxy-4,5-diméthyldi benz [cd, flindole, le (+) - (4S-5aS) -4,5,5a, 6-tétrahydro-9, 1 0-dihydr-oxy-4,5-diméthyldibenz [cd, faindole, le (-) - (4R, 5aR) -4,5,5a, 6-tetra-hydro-9, 1 0-dihydroxy-4,5-dimethyldibenz [cd, f] indole, the (-) - (4S, 5aR) -5- ethyl-4,5,5a, 6-tetrahydro-9, O-dihydroxy-4-methyldi- benz [cd, f] indole, le (-) - (4R, 5aS) -9, 1 0-di- (p -chlorobenzoyloxy) -5 ethyl-4,5,5a, 6-tetrahydro-4-methyldibenz [cd, f] indole,

   (+) - (4S, 5aR) -9,10-di- (3,4-dimethoxybenzoloxy) -5-ethyl-4,5,5a, 6-tetra hydro-4-methyldibenz [cd, f] indole, le (-) - (4S, 5aR) -9, 1 0-di- (o chlorobenzoyloxy) -5-ethyl-4,5,5a, 6-tétrahydro-4-méthyldi- benz [cd, flindole, le (+ ) - (4S, 5aR) -9, 1 0-di- (p-methoxybenzoyloxy) -5-ethyl-4,5,5a, 6-tetrahydro-4-methyldibenz [cd, f] indole, the (+ ) (4S, 5aR) -9, 1 0-di- (p-methylbenzoyloxy) -5-ethyl-4,5,5a, 6-tétra- hydro-4-méthyldibenz [cd, flindole, le (-) - ( 4S, 5aR) -9, 10-dibenzoyl-oxy-4,5,5a, 6-tetrahydro-4,5-dimethyldibenz [cd, f] indole, le (- (4S, SaR) -9, 1 0-diisobutyryloxy -4,5,5a, 6-tetrahydro-4,5-dimethyldi- benz [cd, flindole, le (+) - (4S, 5aR) -9,

   1 0-dibenzoyloxy-5-ethyl- 4,5,5a, 6-tetrahydro-4-methyldibenz [cd, f] indole, the (-) - (4S, 5aR) -5ethyl-4,5,5a, 6- tetrahydro-4-methyl-9, 1 0-dipivaloyloxydibenz [cd, ffindole, le () - (4S, 5aR) -9,10-di- (p-methoxyphenylacetyloxy) -5- ethyl-4,5,5a, 6 -tetrahydro-4-methyldibenz [cd, ndole, le (- (4S, 5aR) -9,10-di- (p-chlorophenylacetyloxy) -5-ethyl-4,5,5a, 6-tetra hydro-4-methyldibenz [cd, flindole, (-) - (4S, 5aR) -9, 1 0-di- (ochlorophenylacetyloxy) -5-ethyl-4,5,5a, 6-tetrahydro-4-methyldibenz [cd, f] indole and (-) - (4S, 5aR) -4,5,5a, 6-tetrahydro-4,5-dimethyl 9,10-di (phenylacetyloxy) dibenz [cd, flindole.    



   20.  4,5,5a, 6-Tetrahydrodibenz [cd, f] indole according to claim 1, characterized in that it is (+) - (4S, 5aR) -9,10-di- (p chlorobenzoyloxy) -5-ethyl-4,5,5a, 6-tetrahydro-4-methyldi- benz [cd, flindole.    



   21.    4,5,5a, 6-Tetrahydrodibenz [cd, flindole according to one of claims 1 to 20, characterized in that it is in the form of an acid addition salt. 



   22.  Medicinal product, characterized in that it contains, as active principle, alone or in combination with pharmaceutically acceptable excipients and vehicles, a 4,5,5a, 6-tetrahydrodi benz [cd, fXindole specified in l One of claims 1 to 14 and 19 or 20, in the free base state or in the form of a pharmaceutically acceptable acid addition salt. 



   The subject of the present invention is new phenanthrene derivatives and the drugs containing these compounds. 



   The invention relates to phenanthrene derivatives, in this case 4,5,5a, 6-tetrahydrodibenz [cd, flindoles having, in one or both of the condensed benzene rings, at least one oxy substituent chosen from hydroxy, acyloxy and ether groups, at least one of these oxy substituents being a hydroxy or acyloxy group when the molecule is unsubstituted in position 4. 



   The oxy substituent (s) may for example be a hydroxy group or a group capable of being hydrolyzed under physiological conditions into a hydroxy group, for example an acyloxy group.  It can also be an ether group.  Advantageously, position 4 is substituted, for example by a cycloalkyl or alkyl group. 



   The compounds of the invention advantageously contain up to 4 oxy substituents, preferably 2 oxy substituents.  The oxy substituents are advantageously found in positions 9 and / or 10. 



   More particularly, the invention relates to the compounds of formula I
EMI2. 2
 in which
   R1 represents a hydrogen atom, an alkyl group containing from I to 10 carbon atoms, a cycloalkyl group containing from 3 to 7 carbon atoms or a cycloalkylalkyl group in which the cycloalkyl radical contains from 3 to 7 carbon atoms and the alkyl residue contains from I to 4 carbon atoms. 



   R2 represents an alkyl group containing from 1 to 5 carbon atoms, and
 the substituents R3 are identical and represent a hydroxy or acyloxy group. 



     R1 preferably represents an alkyl group.  When R1 represents an alkyl group, the latter advantageously contains from 1 to 6 carbon atoms and can signify, for example, the methyl group. 



   R2 advantageously signifies an alkyl group containing from 1 to 4 carbon atoms, preferably from 1 to 3 carbon atoms. 



   The substituents R3 preferably represent an acyloxy group.  These groups can correspond to the formula Ra - CO - O -, in which Ra represents an optionally substituted alkyl group, a cycloalkyl group containing from 3 to 7 carbon atoms, a phenyl residue or a 5 or 6 membered heterocycle. 



   When Ra represents an alkyl group, the latter may advantageously contain from 1 to 17 carbon atoms, preferably from 1 to 7 carbon atoms, and may be straight or branched chain. 



   Ra can represent a substituted alkyl group, the alkyl chain of which advantageously contains from 1 to 5 carbon atoms.  It is advantageously a monosubstituted alkyl group.  Examples of substituents that may be mentioned are halogens, a phenyl residue and carboxy, hydroxy, amino, alkylamino groups containing from 1 to 4 carbon atoms, alkoxy containing from 1 to 4 carbon atoms, dialkylamino in which the alkyl radicals each contain from 1 to 4 carbon atoms, alkylthio containing from 1 to 4 carbon atoms, phenoxy, I-pyrrolidinyl, piperidino or morpholino; advantageously, the substituent is a phenyl residue.    R, can also represent an alkyl group containing from 1 to 4 carbon atoms and substituted by a cycloalkyl group containing from 3 to 7 carbon atoms. 

 

   When Ra represents a phenyl radical or an alkyl group substituted by a phenyl radical, the phenyl radical in question may be an unsubstituted phenyl group, a phenyl group substituted by 1, 2, or 3 identical or different substituents chosen from atoms halogen and trifluoromethyl groups, alkyl containing from 1 to 4 carbon atoms, alkoxy containing from 1 to 4 carbon atoms, alkylthio containing from 1 to 4 carbon atoms and dialkylamino in which the alkyl radicals each contain from I to 4 carbon atoms , or



  a phenyl group substituted with a methylenedioxy group.  The phenyl group is preferably mono- or disubstituted. 



   When Ra represents an alkyl group substituted by a phenyl residue, Ra preferably means a benzoyl group.  The nucleus of the phenyl radical may carry substituents chosen, for example, from halogen atoms and alkyl groups containing from 1 to 4 carbon atoms, alkoxy containing from 1 to 4 carbon atoms and alkylthio containing from 1 to 4 carbon atoms . 



   When Ra represents a heterocycle, it is preferably a heterocycle containing an oxygen, nitrogen or sulfur atom as the only heteroatom, such as, for example, pyridine, thio phene or furan. 



   R, preferably signifies an alkyl group containing from 1 to 7 carbon atoms, a cycloalkyl group containing from 3 to 6 carbon atoms, an unsubstituted phenyl group, a phenyl group mono- or disubstituted by a chlorine or fluorine atom , by a trifluoromethyl group or by an alkyl or alkoxy group containing from 1 to 4 carbon atoms, a benzyl group or a benzyl group mono- or disubstituted by a chlorine or fluorine atom or by an alkyl or alkoxy group containing 1 to 4 carbon atoms. 



   By halogen is meant chlorine, bromine or fluorine, preferably chlorine or fluorine. 



   The groups of representative compounds are those corresponding to formula I '
EMI3. 1
 in which R2 has the meaning already given, and to formula I "
EMI3. 2
 in which R2 has the meaning already given and the substituents R ', are identical and represent an alkyl group containing from 1 to 17 carbon atoms optionally substituted, a cycloalkyl group containing from 3 to 7 carbon atoms, a phenyl residue or a heterocycle with 5 or 6 links. 



   R2 advantageously signifies an alkyl group containing from 1 to 4 carbon atoms.    R ', advantageously signifies an alkyl group containing from 1 to 4 carbon atoms, a cycloalkyl group containing from 3 to 7 carbon atoms, a cycloalkylalkyl group in which the cycloalkyl residue contains from 3 to 7 carbon atoms and the alkyl residue contains 1 or 2 carbon atoms, a phenyl group, a phenyl group monosubstituted by a chlorine atom or by a methoxy group, or a benzyl group. 



   To prepare, for example, 4,5,5a, 6-tetrahydrodibenz [cd, flindoles containing at least one hydroxy or acyloxy substituent in one or both of the condensed benzene rings, the procedure is as described below:
 a) to prepare the compounds containing at least one hydroxy substituent in one or both of the condensed benzene rings, the ether group (s) is split into the corresponding compounds containing, in one or both of the condensed benzene rings , at least one ether group capable of being split, or
 b) to prepare the compounds containing at least one acyloxy substituent in one or both of the condensed benzene rings,

   the corresponding compounds containing at least one hydroxy substituent are acylated in one or both of the condensed benzene rings. 



   A process for the preparation of the compounds of formula I is characterized in that a) for preparing the compounds of formula la
EMI3. 3
 in which R, and R2 have the meanings already given, the ether groups Z are split into a compound of formula II
EMI3. 4
 in which R1 and R2 have the meanings already given, and Z signifies an ether group capable of being split, or
 b) to prepare the compounds of formula Ib
EMI3. 5
 in which R 1 and R 2 have the meanings already given and the substituents R ′ 3 are identical and signify acyloxy groups, the compounds of formula Ia mentioned above are acylated. 



   The splitting of the ether groups according to the process, in particular according to the process described under a, can be carried out according to the methods usually used to split the ether groups.  The reaction can be carried out, for example, by treating the starting materials with a strong mineral acid, for example hydrobromic acid or hydroiodic acid, at a temperature of at least 100 ° C., preferably at a temperature between 100 " C and the boiling point of the reaction mixture, in particular at 130 "C.     The ether group (s), in particular the Z groups, are preferably arylalkoxy or alkoxy groups containing up to 10 carbon atoms, in particular a benzyloxy, ethoxy or methoxy group, preferably a methoxy group. 



   The acylation according to the process, in particular according to the process described under b, can be carried out according to known methods for selectively acylating the phenolic groups in the presence of an amine function.  As acylating agent, one can for example use a functional derivative of an acid such as an acid chloride, an acid bromide or an acid anhydride.  Advantageously, the acid chloride is reacted in the presence of trifluoroacetic acid at a temperature between 20 "C and the boiling point of the reaction mixture, or in the presence of pyridine at a temperature between 0 ° C and ambient temperature. 

 

   To prepare 4,5,5a, 6-tetrahydrodibenz [cd, flindoles containing at least one ether group in one or both of the condensed benzene rings which serve as starting materials in process a and some of which also constitute the end products of the invention,
 c) reducing the double bond located in position Sa, 6 of a 4,5-dihydrodibenz [cd, corresponding flindole, correspondingly substituted, or substituted by an oxo group in position 4 when it is desired to obtain an unsubstituted compound in position 4. 



   The compounds of formula II can be prepared in particular by reducing the double bond located in position 5a, 6 and, when it is present, the 4-oxo group of the compounds of formula III
EMI3. 6
  in which R2 and the groups Z have the meanings already given and either X signifies a hydrogen atom and, in this case, Y is identical to R1, or X and Y together form an oxo group. 



   One can proceed according to the methods usually used to reduce enamines or imines, for example with zinc in an aqueous mineral acid, preferably hydrochloric acid, optionally in the presence of a mercuric salt, for example mercuric chloride.  The operation is advantageously carried out in an organic solvent, for example in a lower alkanol, such as ethanol, at a temperature between SOC C and the boiling point of the reaction mixture.  Under these conditions, the 4oxo group possibly present is reduced simultaneously. 



   The compounds of the invention thus obtained can then be isolated and purified according to the usual methods.  If necessary, the free bases can be transformed into their acid addition salts; from salts.  the bases can be released according to known methods. 



  The acids suitable for the formation of the salts are hydrochloric acid, hydrobromic acid and methanesulphonic acid. 



   The compounds of the invention have an asymmetric carbon atom in position 5a and can be obtained in the form of racemates or in one of the optically active forms, for example in the form of an individual enantiomer. 



   When the molecule is substituted in position 48, in particular when in the formula IR, has a meaning other than hydrogen, the compounds of the invention have 2 asymmetric carbon atoms in positions 4 and 5a, and there may therefore exist 2 racemic.    When optically active starting materials are used, optically active end products are obtained.  Starting from racemic starting materials, racemic end products are obtained.     From the individual racemates, the enantiomers can be separated according to known methods, for example by fractional crystallization of the diastereomeric salts, for example the salts which they form with (+) - or (-) - tartaric acid or the di-p-toluoyl acid - (+) - or - (-) - tartaric. 

  The resolution of racemates can be done after the final synthesis or possibly at a previous stage.  The isomers are preferably separated before the ether groups are removed. 



   The monosubstituted starting products in position 4 used in process c, in particular the compounds of formula III in which
X represents hydrogen and Y is different from hydrogen, has an asymmetric carbon atom in position 4.  When these compounds are reduced, a second asymmetric carbon atom is formed in position 5a. 



   The compounds of formula IIIa
EMI4. 1
 in which R2 and the groups Z have the meanings already given, can be prepared according to the following reaction scheme:
EMI4. 2

 In the reaction scheme, the groups Z and R2 have the meanings already given, R'2 represents a hydrogen atom or an alkyl group containing from I to 4 carbon atoms, Hal signifies iodine, bromine or chlorine and Alk means a lower alkyl group.  The reactions can be carried out in a known manner. 



   The compounds of formula V can be prepared according to a modification of the Curtius reaction, for example by reacting the acid of formula IV with sodium azide in the presence of trifluoroacetic acid and trifluoroacetic anhydride and then hydrolyzing with a base.  The acylation of the compounds of formula V can be carried out for example with a compound of formula R "2 - CO - Hal where Hal has the meaning already given and R" 2 represents an alkyl group containing from 1 to 4 carbon atoms, in presence of an acid acceptor, for example N-ethyldiisopropylamine.  When R'2 represents hydrogen, the reaction can 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 can be reduced, for example with diborane. 

  The preparation of the compounds of formula VIII can advantageously be carried out by reacting the compound of formula VII with a chloroformate in an organic solvent, in the presence of an acid-accepting agent, for example N-ethyldiisopropylamine.  The compounds of formula IIIa are then obtained by treating the compounds of formula VIII for example with an alkyl- or aryllithium, preferably n-butyllithium or tert. -butyllithium, in a mixture of tetrahydrofuran and hexane at a temperature between - 110 and 0aC.    



   The starting materials substituted in position 4 with an oxo group and used in process c, other than those of formula IIIa, can be obtained in a similar manner to that described above for the compounds of formula IIIa. 



   To prepare the compounds of formula lIlb
EMI5. 1
 in which the groups Z, R and R2 have the meanings already given, one can proceed according to the following reaction scheme:
EMI5. 2

 The substituents Z, R1, R2 and Hal have the meanings already given, and Ane means an anion.  The reactions can be carried out according to known methods. 



   The acylation of the compounds of formula V can be carried out for example with a compound of formula Hal-CO- R'1 where R 'is identical to Rl but cannot signify hydrogen and Hal has the definition already given, in the presence of an acid acceptor, for example N-ethyldiisopropylamine.  When R1 signifies hydrogen, the reaction can 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 can advantageously be alkylated with an alkyl iodide under the conditions of a phase transfer reaction by catalysis, for example in the presence of tetrabutylammonium hydrogen sulfate. 

  By treating the compounds of formula X for example with n-butyllithium or tert. -bjityl- lithium in a mixture of tetrahydrofuran and hexane, at a temperature between - 110 and o C, the compounds of formula XI are obtained.  The dehydration of the compounds of formula XI can be carried out for example using a mineral acid, for example hydrochloric acid in ethereal solution.  The salts of formula XII can then be reduced to compounds of formula IIIb by means of sodium borohydride in tetrahydrofuran. 

 

   The compounds of formula X can also be prepared by acylation of the compounds of formula VII with compounds of formula R1 -CO-Hal, as described above. 



   The compounds of formula XI in which R1 signifies R'l, as defined above, can also be prepared by reacting the compounds of formula IIIa with compounds of formula R'1 -Li where R'l has the meaning already given.  The compounds of formula XI where R1 signifies hydrogen can be prepared by reduction of the compounds of formula IIIa with LIAIT4.    



   The compounds of formula IIIb in which R1 represents a methyl group can also be prepared according to the following reaction scheme:
EMI5. 3

IIIb (where R1 means CH3)
 In these compounds, the substituents Z and R2 have the meanings already given, Hale represents chlorine, bromine or iodine, Ane signifies a chloride, bromide, iodide ion, CH3 504e or C2H1SO4e, and either R, signifies hydrogen and, in this case, Ry represents a bromomethyl group, that is R, and Ry together form a residue = CH2.    



   The alkylation of the compounds of formula XIII can for example be carried out by reaction with compounds of formula An - R2 where R2 has the meaning already given and An represents chlorine, bromine or iodine, or with dimethyl sulphate or of diethyl, when R2 represents a methyl or ethyl group.  The ring opening in the compounds of formula XIV can be carried out according to known methods, by reaction with an alkali metal alcoholate, preferably tert. -potassium butylate in dimethoxyethane, dioxane or tetrahydrofuran, at a temperature between 0 and 50 C, preferably at room temperature. 



   The preparation of the compounds of formula XVI from the compounds of formula XV can be carried out under oxidation conditions, for example with bromine or with a halogen-releasing compound, for example N-bromosuccinimide.  The regioselective cyclofunctionalization of the compounds of formula XV into compounds of formula XVI in the presence of bromine can be carried out at a temperature between 0 and SOC, preferably at room temperature, advantageously in an inert organic solvent, for example a halogenated hydrocarbon such as methylene chloride, chloroform or carbon tetrachloride, preferably chloroform. 

  The reaction with N-bromosuccinimide can advantageously be carried out at a temperature between 0 and 50 C, preferably at room temperature, in the presence of water and optionally an organic solvent such as dioxane, tetrahydrofuran, chloride methylene or chloroform.  For the demethylation of the quaternary compounds of formula XVI, followed by a rearrangement, it is advantageously possible to operate at a temperature above 80 ° C., preferably between 80 and 110 ° C., in particular at 100 ° C., in an organic solvent, for example benzene, dimethylformamide or ethaaolamine, preferably ethanolamine. 



   To prepare the other starting materials used under c, in which the position 4 is not substituted or is substituted by a substituent R1 other than hydrogen, one can proceed in a similar manner to that described for the preparation of the compounds of formula IIIb. 



   The products obtained according to the above reactions can be isolated and purified in a known manner. 



   The starting materials whose preparation is not described are known or can be prepared according to known methods, from known products or in a manner analogous to those described in the present patent. 



   It should be noted that some of the above compounds may be in an optically active form. 



   Some of the starting materials are new and constitute intermediate products which are particularly useful for the preparation of compounds having pharmacological activity. 



   Thus, the following compounds, because of the functional groups present, for example the ether groups, the oxo groups, the double bond in position Sa, 6, are interesting intermediate products:
 a) 4,5,5a, 6-tetrahydrodibenz [cd, flindoles comprising at least one ether group on one of the two condensed benzene rings, the ether groups having to be located on the same condensed benzene ring when the molecule contains more d 'an ether group,
 b) 4,5-dihydrodibenz [cd, flindoles comprising at least one hydrogen atom linked to the carbon atom located in position 4 and at least one ether group capable of being split, located in one of the positions 1 to 3 and 7 to 10 of the molecule, and
 c) 4,5-dihydro-4-oxodibenz [cd, flindoles containing only one or two ether groups capable of being split,

   located in one of positions 7 to 10, the molecule being free from other oxy substituents. 



  More particularly, the compounds of formula III'a
EMI6. 1
 in which R2 has the meaning already given, the ring B having only one or two ether groups capable of being split, and the molecule having no other substituent oxy, the compounds of formula III'b
EMI6. 2
 in which R1 and R2 have the meanings already given, the rings A and / or B containing at least one ether group capable of being split, and the compounds of formula V '
EMI6. 3
 in which Hal has the meaning already given, the rings A and / or B containing at least one ether group capable of being split (of which the compounds of formulas IIIa, IIIb and V constitute examples) are intermediate products which are particularly suitable for the preparation of a large number of compounds, because of the functional groups which they contain,

   in particular the ether and amino groups and the halogen atom. 



   The intermediate products described above advantageously include 2 ether groups, for example located in positions 9 and 10. 



  The ether group (s) are preferably alkoxy groups containing from 1 to 4 carbon atoms. 



   The following examples illustrate the present invention without in any way limiting its scope.  The temperatures are all indicated in degrees Celsius and are given uncorrected. 



   The absolute configurations of the optically active compounds of formula II, corresponding to Example 7 and in which Z represents a methoxy group and Rl and R2 each signify a methyl group, were determined by X-ray analysis.  The absolute configuration of the other optically active compounds of formula II has been established by analogy on the basis of their rotary power.  The compounds of formula I have been assigned the same absolute configuration as that of the compounds of formula II used in their preparation. 



  Example 1: (5aRS) -4,5,5a, 6-Tetrahydro-9, 1O-dimethoxy-5-methyldt'benz [cdf] -
 indole
 While stirring, 544 ml (0.06 mol) of a 3% aqueous solution of mercuric chloride to 272 g (41.7 mol) of zinc powder are added under a nitrogen atmosphere and the whole is stirred for a further 5 min at room temperature.  To this mixture is added a suspension of 40 g (0.316 mol) of 4, S-dihydro-9, 10-dimethoxy-S-meth-yl-4-oxodibenz [cd, flindole in 544 ml of ethanol as well as 3400 ml 2N hydrochloric acid.  The reaction mixture is heated to 65 and kept at this temperature for 30 min.  After adding 272 ml of 37% hydrochloric acid, the mixture is stirred at 65 for 16 h.  

  After cooling to 10, the suspension is filtered and the zinc powder is washed with 1600 ml of an equal parts mixture of methylene chloride and ethanol.  The filtrate is cooled by an ice bath, it is made alkaline with concentrated ammonia and it is extracted three times with, each time, 2000 ml of methylene chloride.  The organic phases are combined, the overall solution is dried, filtered and evaporated, which gives the (5ARS) -4,5,5a, 6-tetrahydro-9,10-dimethoxy-5-methyldibenz [cd, f] indole; it melts at 126-128 with decomposition, after recrystallization from ether. 



   NMR spectrum 1. 00 MHz (CDCl3): # 2.66 ppm (3H, s, M
CH3), 4.25 (1H, d, 11Hz, C-4aH).    



   To prepare the 4,5-dihydro-9,10-dimethoxy-5-methyl-4-oxodi-benz [cd, f] indole used as starting material, the procedure is as described below. 



   a) Qn adds.  spus nitrogen atmosphere and at room temperature, a mixture of 860 ml (6.16 mol) of trifluoroacetic anhydride and 860 ml (11.24 mol) of trifluoroacetic acid to 140 g (0.380 mol) of acid 8-bromo-3,4-dimethoxyphenanthrene-9-carboxy and this mixture is stirred for 10 min.  After cooling to -5 'the clear mixture br. one thus obtained, 30.4 g (0.468 mol) of sodium azide in the solid state are carefully added thereto.  After
 having stirred the whole for 3 h at 2 ", the reaction mixture is poured onto ice, the suspension thus obtained is filtered and washed with
   1.4 I of water. 

  The crude white product thus obtained is suspended in 2.5 I methanol and this mixture is heated to reflux.  After adding 1680 ml of 2N sodium hydroxide, the mixture is heated to
 reflux for 45 min the clear yellow solution obtained.  We refrain
 then says the solution at room temperature, it is extracted with methylene chloride, the organic phase is dried and evacuated
 pore.  The 9-amino-8-bromo-3,4-dimethoxyphenanthrene thus obtained melts at 107-108 '.    



   b) 19.4 ml are added dropwise over 5 min.
 (0.346 mol) formic acid to a suspension of 64.5 g (0.397 mol)
 of N, N-carbonyldiimidazole in 387 ml of tetrahydrofuran
   anhydrous and the whole is stirred for 30 min at the am-
 biante. 

  This solution is then added dropwise, at 0-3 and in the course of 5 min, to a solution of 100 g (0.301 mol) of 9-amino-8
 bromo-3,4-dimethoxyphenanthrene in 1600 ml of tetrahydrofu--
 ranne and this mixture is stirred for 16 h; After cooling to
   10, the mixture is filtered, the crystals are washed with ether and dried under reduced pressure: 8-bromo-9-formylamino-3,4-
 dimethoxyphenanthrene thus obtained mows at 191-193. 



   c) To a suspension of 90 g (0.249 M) of 8-bromo-9-formyl-
 amino-3,4-dimethoxyphenanthrene in 900 ml of tetrahydrofu
 anhydrous ranne, quickly added, under a nitrogen atmosphere,
 1000 ml (1.0 mol) of a molar solution of diborane in tetra
 anhydrous hydrofuran.  The resulting solution is heated to reflux
 for 4 V2 h, then it is stirred at room temperature for
 4 p.m.  After having cooled the mixture to at -5, it is added dropwise to
 drop, within 5 min, 1800 ml of 2N sodium hydroxide. 



   The reaction mixture is heated to reflux, the tetrahydrofuran is evaporated at atmospheric pressure, 900 ml of etha are added.
 nol in hot aqueous solution, then methanol is evaporated under
 normal pressure in a rotary evaporator This operation - adding 900 ml of ethanol followed by evaporation - is repeated
 three times.  The solid yellow residue is added to a
 mixture of 900 ml of methylene chloride and 900 ml of baby water
 agitates the presence of 900 ml of ice. 

  The organic phase is separated,
 the aqueous phase is extracted three times with, each time,
 900 ml of methylene chloride, the organic phases are combined,
 dry the resulting overall solution and evaporate, emulsify
 then the oil obtained in approximately 500 ml of hot methanol and -on
 add methylene chloride to form a solution of about
   11.     The methylene chloride is removed by heating the solution in
 a rotary evaporator while ensuring that it does not form two
 phases.  After cooling to -10, 8-bromo-9 is obtained
 methylamino-3,4-dimethoxyphenanthrene melting at 75-77. 



   d) 70 g (0.202 mol) of 8 g are dissolved under a nitrogen atmosphere
 bromo-9-methylamino-3,4-dimethoxyphenanthrene in 700 ml of
 anhydrous methylene chloride and 139 ml (0.808 mol) of
 N-ethyldiisopropylamine and 38 ml (0.404 mol) of chloroformate
 ethyl.    After stirring the reaction mixture at temperature
 ambient for 16 h, it is extracted with 500 ml of 2N hydrochloric acid, the organic phase is separated and stirred with 500 ml of a saturated solution of sodium bicarbonate.  The aqueous phase is extracted three times with 250 ml of metal chloride each time
 thylene, the organic phases are combined, the overall solution is dried
 resulting, it is evaporated and the ethyl chloroformate is removed.
 duaire by heating to 70 'under reduced pressure. 

  After crystallization
 in a mixture of ether and petroleum ether, 8bromo-9- (N-ethoxycarbonyl-N-methyl) amino-3,4-dimethoxyphen is obtained
 anthrene melting at 109-110. 



   e) To a solution of 70 g (0.167 mol) of 8-bromo-9- (N-ethoxy-
 carbonyl-N-methyl) amino-3,4-dimethoxyphenanthrene in
 1890 ml of tetrahydrofuran and 630 ml of n-hexane,
 within 10 min, at - 105? under agitation and under atmosphere
 nitrogen, -101.8 ml- (0.167 mol) of a 1.64M solution of n-butylli
 thium in hexane.  Continue to stir the reaction mixture
 at the same temperature for 25 min, then the temperature is allowed to return to + 10.     After adding 200 ml of water with precau
 tion, the reaction mixture is further diluted with 1500 ml of water and
 extract three times with 1500 ml of methylene chloride each time. 

  The combined organic phases are dried, filtered and
 evaporates them, which gives 4,5-dihydro-9,10-dimethoxy-5-methyl-4-
 oxodibenz [cd, f] indole melting at 151-152 (after recrystallization
 in a mixture of ether and petroleum ether). 



   Example 2:
 By proceeding as described in Example 1 and using the appropriate starting materials.  of formula IIIa, the
 following compounds of formula II:
 -le (5aRS) -5-ethyl-4,5,5a, 6-tetrahydro-9,10-dimethoxydibenz
   [cd, flindole. (in the form of an oil)
 NMR spectrum 60 MHz (CDCl3): 6 4.40 ppm (1H, dd, 10Hz and
 homoallyl coupling of 1Hz, C-4 α H).    1.3 (3H, t, 7Hz, NCHvCH3)
 - (5aRS) -4yS, Sa, 6-tetrahydro-9f 10-dimethoxy-5-n-propyldi-
 benz [cd, f] indole (in the form of an oil)
 NMR spectrum 60-MHz (CDCl3):

   6 4.40 ppm (1H, dd, 10Hz and
 homoallyjic coupling-1Hz, C4aH), 1.00 (3H, t, 7Hz,
 NCH2CH2CH3)
 To prepare the products.  departure we can proceed as
 described below:
 a) To a solution of 100 g (0.302 mol) of 9-amino-8-bromo-3,4-
 dimethoxyphenanthrene in 500 ml of methylene chloride, -on
 add 110 ml (0.638 mol) of N-ethyldiisopropylamine.  To the mixture
 thus obtained, drop by drop, over the course of 20 min, a
 solution of 41.6 ml (0.585 mol) of acetyl chloride in 500 ml of
 methylene chloride-During the addition, on. maintains the temperature of the reaction mixture at 20 by cooling with a bath
 of ice. 

  The reaction mixture is stirred for 16 h at room temperature.
 ambient temperature, it is then poured into 2N hydrochloric acid. and extracted with methylene chloride.  We wash the organ phase
 picnic with 2N sodium hydroxide solution and with water,
 it is dried and evaporated.     9-acetylamino-8 is thus obtained
 bromo-3,4-dimethoxyphenanthrene melting at 200-202 after recris
 tallization in ether.    

 

   By proceeding in a similar manner, we obtain.  8-bromo-3,4-
 dimethoxy-9-propionylaminophenanthrene melting at 192-193. 



   b) By proceeding as described in examples lc to le, one can
 prepare the following compounds;
 - 5-ethyl-4,5-dihydro-9,10-methoxy-4-oxodibenz [cd, f] indole (F.  = 125-126 with decomposition);
 -4,5-dihydro-9,10-dimethoxy-4-oxo-5-n-propyldibenz [cd, f]
 indole (F.  = 103-105 with decomposition). 



   Example 3: 5-Ethyl-4,5,5a, 6-tétral2ydro-9, I0-dinÉthoxy-4-méthyldibenzlcdf] -
 indole
 a) 8-Bromo-9-ethylamino-3,4-dimethoxyphenanthrene
 By proceeding as described in example le, the 9-acetyl is reduced
 amino-8-bromo-3,4-dimethoxyphenanthrene using diborane, which gives the 8-bromo-9-ethylamino-3,4-dimethoxyphenanthrene melting at 103-105 after recrystallization from ether. 



  b) 9- (N-A cetyl-N-ethyl) amino-8-bromo-3,4-dimethoxyphenanthrene
 By proceeding as described in Example 2a, the 8bromo-9-ethylamino-3,4-dimethoxyphenanthrene is reacted with acetyl chloride.  There is thus obtained 9- (N-acetyl-N-ethyl) amino-8-bromo-3,4-dimethoxyphenanthrene melting at 189 after recrystallization from ethyl acetate. 



  c) (4RS) -5-Ethyl-4,5-dihydro-4-hydroxy-9,10-dimethoxy-4-methyl dibenz [cdfjindole
 i) At a temperature of -105, 10 ml (20 mM) of a 2M solution of tert are added. -butyllithium in pentane to a solution of 4.04 g (10 mM) of 9- (N-acetyl-N-ethyl) amino-8-bromo-3,4-dimethoxyphenanthrene in 130 ml of anhydrous tetrahydrofuran and 50 ml of n-hexane.  The temperature of the reaction mixture is allowed to return to room temperature and the mixture is poured onto ice.  After extraction with methylene chloride, the organic phase is washed with water, dried and evaporated. 

  (4RS) -5-ethyl-4,5-dihydro 4-hydroxy-9,10-dimethoxy-4-methyldibenz is used directly for the following reaction [cd, crude ff, crude, obtained in the form of a foam yellow brown. 



   ii) To a solution of 1 g (3.3 mM) of 4,5-dihydro-9,10-dimeth oxy-5-ethyl-4-oxodibenz [cd, flindole (prepared as described in Example 2b) in 30 ml of anhydrous tetrahydrofuran, 2.1 ml (3.3 mM) of an ethereal solution containing 5% methyllithium are added dropwise at a temperature of - 60 ".  The temperature of the reaction mixture is allowed to return to ambient temperature and is kept at this temperature for 30 min.  The mixture is made alkaline with a 2N solution of sodium hydroxide, extracted with methylene chloride, the organic phase is dried and evaporated. 

  This gives (4RS) -5-ethyl-4,5-dihydro-4-hydroxy-9,10-dimethoxy-4-methyldibenz [cd, flindole in the form of a dark green oil [IR spectrum (CH2CI2) : 3550 cm- '(OH)].  The crude product is used directly for the next reaction. 



  d) 5-Ethyl-9,10-dimethoxy-4-methoxy-4-methyldiben chloride [cdf] -
 indolinium
 To a solution of 3.2 g (10 mM) of (4RS) -5-ethyl-4,5-dihydro-4 hydroxy-9,10-dimethoxy-4-methyldibenz [cd, crude ffindole in 30 ml of ether , 2 ml (10.5 mM) of ether saturated with hydrochloric acid are added, which causes the precipitation of a red product.  The mixture is stirred for 30 min and the product is filtered.  5-ethyl-9,10-dimethoxy-4-methyldibenz chloride [cd, flindolinium is thus obtained, which is used directly for the following reaction. 



  c) (4RS) -5-Ethyl-4,5-dihydro-9,10-dimethoxy-4-methyldibenz [cd, f]
 indole
 To a solution of 12.5 mg (0.33 mM) of sodium borohydride in 3 ml of anhydrous tetrahydrofuran and 3 ml of ethanol, 100 mg (0.33 mM) of 5-ethyl-9 chloride are added, 10-dimethoxy-4-methyl-dibenz [cd, flindolinium.     After the reaction mixture has reacted violently, the mixture is stirred for 15 min, 3 ml of water are added, then the mixture is extracted with methylene chloride.  The organic phase is washed with water, dried and evaporated, giving (4RS) -5-ethyl-4,5-dihydro-9, 1 O-dimethoxy-4-methyldibenz [cd , fl- indole in the form of a green oil. 



   NMR spectrum 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 (1H, q, 7Hz, C-4-H), 6.2 (1H, s, C-6-H), 8.98 (1H, d, 8Hz, C-I-H).    



  IR spectrum (CH2CI2): 1635 cm- '
EMI8. 1
   f) 5-Ethyl-4,5,5a, 6-tetrahydro-9, JO-dlmethoxy-4-methylslihenzfcdfT
 do the
 By proceeding as described in Example 1, the (4RS) 5-ethyl-4,5-dihydro-9,1 O-dimethoxy-4-methyldibenz [cd, f] indole is reduced, which gives a mixture of the two (4R *, SaS *) and (4R *, SaR *) racemates of the title compound (as an oil).  The individual racemates can be separated by chromatography on silica gel. 



   i) (+) - (4R *, 5aS *):
 100 MHz NMR spectrum (CDCl3): 8 1.42 (3H, d, 6Hz, C-4a-
CH3). 



   ii) (+) - (4R *, SaR *):
 100 MHz NMR spectrum (CDCI3): 8 1.18 (3H, d, 7Hz, C-4- CH3).    



  Example 4:
 By proceeding as described in Examples 3a to 3e and using the appropriate starting materials, the (4RS) -4,5-dihydro9,10-dimethoxydibenz [cd, flindoles of formula IIIb below in which R1 and R2 have the meanings are obtained given in the table (the free bases of formula IIIb having an NMR spectrum, the characteristic data of which are similar to those described in Example 3e, are obtained in the form of an oil. 



   Table 1:
EMI8. 2


 <tb> Example <SEP> R,
 <tb> <SEP> I <SEP> CH3 <SEP> CH3
 <tb> <SEP> II <SEP> CH3 <SEP> n-C3H
 <tb> <SEP> III <SEP> CH3 <SEP> iso-C3
 <tb> <SEP> IV <SEP> CH3 <SEP> n-C4H
 <tb> <SEP> V <SEP> C2H5 <SEP> CH3
 <tb> <SEP> VI <SEP> nC3H7 <SEP> CH3
 <tb> <SEP> VII <SEP> iso-C3H7 <SEP> CH3
 <tb> <SEP> VIII <SEP> n-C4Hg <SEP> CH3
 <tb> <SEP> IX <SEP> sec.-C4Hg <SEP> CH3
 <tb> <SEP> X <SEP> tert.-C4Hg <SEP> CH3
 <tb> <SEP> Xl <SEP> n-C5H11 <SEP> CH3
 <tb> <SEP> XII <SEP> -CH3-CH2-CH3-CH3 <SEP> CH3
 <tb> <SEP> CH3
 <tb> <SEP> CH3
 <tb> <SEP> XIII <SEP> -CH2-C-CH3 <SEP> CH3
 <tb> <SEP> CH3
 <tb> <SEP> XIV <SEP> -CH-CH2-CH3 <SEP> CH3
 <tb> <SEP> C2Hs
 <tb> <SEP> XV <SEP> -n-C0H13 <SEP> CH3
 <tb> <SEP> CH2
 <tb> <SEP> XVI <SEP> -CH <SEP> CH3
 <tb> <SEP> CH2
 <tb>
 By proceeding as described in Example 3b,

   the compounds of formula IIIb are directly transformed into corresponding compounds of formula II in which Z signifies a methoxy group.

 

  Example 5: 4,5,5a, 6-Tetrahydro-9,10-dimethoxy-4,5-dimethyldiben [cdf] indoles a) Iodide of (-) - (6aR) -5,6,6a, 7-tetrahydro- 10,11-dimethoxy-6,6-di
 methyl-4H-dibenzo [de, g] quinolinium
 To a solution of 100 g (0.34 M) of (-) - (6aR) -5,6,6a, 7-tetra- hydro- 10,11-dimethoxy-6-methyl-4H-dibenzo [de, g ] quinoleine in
 100 ml of methylene chloride, 100 ml (1.6 M) of methyl iodide are added and this mixture is heated at reflux for 30 min. After cooling the reaction mixture, ether is added, the precipitate is filtered and dried, giving iodide of (-) - (6aR) 5,6,6a, 7-tetrahydro-10,11- dimethoxy-6,6-dimethyl-4H-dibenzo [de, g] quinolinium (decomposition at 173-176).



     b) (9RS) -9.10-Dihydro-3,4-dmethoxy-9-dimethylamino-8-vinyl-
 phenanthrene
 13.9 g (124 mM) of tert. Are dissolved under a nitrogen atmosphere.



  potassium butylate in 560 ml of tetrahydrofuran and to this solution is added 47 g (112 mM) of iodide of (-) - (6aR) 5,6,6a, 7-tetrahydro-10,11-dimethoxy-6,6 -dimethyl-4H-dibenzo [de, g] quinolinium. The mixture is stirred at room temperature for 1 h, poured onto ice, 560 ml of 10% hydrochloric acid is added thereto and the mixture is washed with ether. The aqueous phase is neutralized with sodium bicarbonate, it is made alkaline at pH 9 with 50 ml of 20% sodium hydroxide and it is extracted three times with 500 ml of methylene chloride each time.



  The methylene chloride extracts are combined, the overall solution is dried and evaporated. The evaporation residue is purified by chromatography on 1 kg of silica gel using ether as eluent. This gives (9RS) -9,10-dihydro-3,4-dimethoxy-9-dimethylamino-8-vinylphenanthrene melting at 109.



  c) (4RS) -4,5-Dihydro-9,10-dimethoxy-4,5-dimethyldibenz [cdf] indole
 To a suspension of 10.2 g (57 mM) of N-bromosuccinimide in 55 ml of water, 17.5 g (57 mM) of (9RS) 9,10-dihydro-3,4-dimethoxy are added with stirring -9-dimethylamino-8-vinylphenanthrene.



  The reaction mixture heats up and after a few minutes the product precipitates. After about 1 hour, the mixture is cooled in an ice bath and the precipitate is filtered. This gives (5aRS) -4,5,5a, 6-tetrahydro-9,10-domethoxy-5,5-dimethylenedibenz [cd, f] indolinium bromide (softening at 135 and melting at 165). The crude product is used directly for the following reaction.



   To 19.7 g (50.7 mM) of the indolinium bromide obtained above, 100 ml of ethanolamine are added and the mixture is stirred at 100 ° C. for 1 h. The reaction mixture is poured onto a mixture of ice and water and it is extracted three times with 300 ml of methylene chloride each time. The combined methylene chloride extracts are dried and evaporated to give (4RS) -4,5-di hydro-9,10-dimethoxy-4,5-dimethyldibenz [cd, findole in the form of an oil.



   (4RS) -4,5-dihydro-9,10-dimethoxy-4,5-dimethyldibenz [cd, f] indole can also be prepared as described below.



   To a solution of 4.8 g (15.5 mM) of (9RS) -9,10-dihydro-3,4-dimethoxy-9-dimethylamino-8-vinylphenanthrene in 45 ml of chloroform, added dropwise, at room temperature, a solution of 2.7 g (0.86 ml; 17 mM) of bromine in 15 ml of chloroform. When the reaction is complete, the mixture is cooled in an ice bath, the precipitate which has formed is filtered and washed with 10 ml of chloroform and 100 ml of ether. 4-bromomethyl-4,5,5a, 6-tetrahydro-9,10-dimethoxy-5,5-dimethyldibenz [cd, f] indolinium is thus obtained (softening at 132 and melting at 154 158). This product is directly transformed into (4RS) -4,5-dihydro-9,10-dimethoxy-4,5-dimethyldibenz [cd, f] indole by heating it in ethanolamine, as described above.



  d) 4,5,5a, 6-Tetrahydro-9,10-dimethoxy-4,5-diméthyldibenz [cdf]
 indole
 400 ml (44.3 mM) of a 3% aqueous solution of mercuric chloride are added to 200 g (330 mM) of zinc powder. The mixture is stirred for 5 min, 2500 ml of 2N hydrochloric acid is added thereto, then a solution of 15.7 g (50 mM) of (4RS) -4,5-dihydro9,10-dimethoxy-4,5- dimethyldibenz [cd, f] indole in 400 ml of ethanol and this mixture is heated to 50-60 for 1 h. After adding 200 ml of 37% hydrochloric acid, the mixture is stirred at 90 for 14 h. The mixture is cooled, the zinc powder is filtered and the filtrate is made alkaline at pH 10 with ammonia.

  The mixture is extracted three times with 1000 ml of methylene chloride each time, the combined methylene chloride extracts are dried over sodium sulphate, then they are evaporated, which gives 4,5,5a, 6-tetrfahydro -9,10-dimethoxy-4,5-dimethyldiben [cd, f] indole in the form
 of a mixture of the two racemates (4R *, 5aS *) and (4R *, 5aR *) under
 form of free bases. Chromatography the mixture of the two ra
 cemic on 1.8 kg of silica gel using, as eluent,
 50 ml fractions of a mixture of methylene chloride and me
 thanol in the 98.5: 5 ratio.



   Fractions 125-240 contain the (#) - (4R *, 5aS *) - 4,5,5a, 6-
 tetrahydro-9,10-dimethoxy-4,5-dimethyldiben [cd, f] indole. Spectrum
 NMR of the free base (CDCl3, 90 MHz): 3 1.44 ppm (3H, d,
 6Hz, C-4a-CH3). The corresponding hydrochloride, obtained according to the
 usual methods, melts from 1850 (with decomposition).



   The fractions 250-330 contain the (#) - (4R *, 5aR *) - 4,5,5a, 6-
   tetrahydro-9,10-dimethoxy-4,5-dimethyldibenz [cd, f] indole. Spectrum
 NMR of the free base (CDCI3, 90 MHz): 3 1.24 ppm (3H, d, 7Hz, C-4ss-CH3). The corresponding hydrochloride, obtained according to the usual methods, melts from 200 (with decomposition).



  Example 6:
 By proceeding as described in Example 5, the following compounds of formula II can be prepared from the appropriate starting materials (the free bases of the compounds of formula II are obtained in the form of an oil): i) (#) - (4R *, 5aS *) - and (#) - (4R *, 5aR *) - 5-ethyl-4,5,5a, 6-tetra hydro-4-methyl-9, 1 0-dimethoxydibenz [cd, ffindole ; il) (+ -) - (4R *, SaS *) - and (+) - (4R *, 5aR *) - 4,5,5a, 6-tetrahydro-4-
 methyl-5-n-propyl-9,, 10-dimethoxydibenz [cd, Qindole; iii) (+) - (4R *, 5aS *) - and (#) - (4R *, 5aR *) - 4,5,5a, 6-tetrahydro-4-
 methyl-5-isopropyl-9,10-dimethoxydiben [cd, f] indole;

   iv) (+) - (4R *, 5aS *) - and) - (4R *, SaR *) - 5-n-butyl-4, 5.5a, 6-tetra-hydro-4-methyl-9, 10 -dimethoxydibenz [cd, flindole.



  Example 7:
 To a solution of 3.3 g (22 mM) of (-) - tartaric acid in 22 ml of a 50/50 mixture of ethanol and ethyl acetate, a solution of 5 g (18 mM) of (#) - (4R *, 5aS *) - 4,5,5a, 6-tetrahydro-9,10-dimethoxy-4,5-dimethyldibenz [cd, f] indole as base in 10 ml d ethyl acetate and 0.5 ml of methanol, and this mixture is stirred for 1 h at room temperature. (-) - (4S, 5aR) -4.5, 5a, 6-tetrahydro-9,1 1 0-dimethoxy-4,5-dimethyldi-benz [cd, ffindole crystallizes. It breaks down to 183-190; [a] 2D = - 120.6 (H2O, c = 0.5).

  (-) - (4S, 5aR) - 4,5,5a, 6-tetrahydro-9,10-dimethoxy-4,5-dimethyldibenz [cd, f] indole hydrochloride, obtained according to the usual methods, decomposes at 210-255; [a] D = 140 (H2O, c = 0.5).



   The mother liquors from the crystallization of tartrate are made alkaline with potassium carbonate and the mixture is extracted with methylene chloride. The combined organic extracts are washed until neutral, dried and evaporated. The residue (about 2.5 g; 9 mM) is mixed with 1.65 g (11 mM) (+) - tartaric acid in 11 ml of an equal parts mixture of ethanol and acetate ethyl. After having stirred for 1 h at room temperature, the (+) -tartrate of (+) - (4R, 5aS) -4,5,5a, 6-tetrahydro-9, 1 0-dimethoxy4,5-dimethyldibenz [cd , f] indole crystallizes. It breaks down in 185 1900; [a] D2o = + 116 (HzO, c = 0.5).

  The hydrochloride of (+) (4R, 5aS) -4,5,5a, 6-tetrahydro-9, O-dimethoxy-4,5-dimethyldibenz- [cd, flindole, obtained according to the usual methods, decomposes at 215- 230; [a] D = + 1400 (H2O, c = 0.5).



   The following compounds can be prepared from (+ -) - (4R *, 5aR *) - 4,5,5a, 6-tetrahydro-9,10-dimethoxy-4,5-dimethyldi benz [cd, fJindole (under free base form):
 (-) - (+) - tartrate - (4S, 5aS) -4,5,5a, 6-tetrahydro-9,10-di methoxy-4,5-dimethyldibenz [cd, flindole,
 decomposition: 177-180; [a] D = + 116 (1120, c = 0.5);
 decomposition of the corresponding hydrochloride obtained according to the usual methods: 160-1645; [&alpha;] D20 = + 1600 (H2O, c = 0.5);
 -the (+) - tartrate of (-) - (4R, 5aR) -4,5,5a, 6-tetrahydro-9,10-dimethoxy-4,5-dimethyldibenz [cd, f] indole,
 decomposition:

  : 178-182; [a] 2D0 = -114 (H2O, c = 0.5);
 decomposition of the corresponding hydrochloride obtained according to the usual methods: 158-162 C; [a] D = -156 (H2O, c = 0.5).



   By following a similar procedure, the following compounds can also be obtained from (+) - (4R *, 5aS *) - 5-ethyl-4,5,5a, 6tetrahydro-9,10-dimethyloxy-4-methyldibenz [ cd, f] indole (in free base form):
 (()) tartrate (+) - (4R, 5aS) -5-ethyl-4,5a, 6-tetrahydro 9,10-dimethoxy-4-methyldibenz [cd, f] indole, [&alpha;] D20 = + 96 (H2O, c = 0.5);
 the corresponding hydrochloride prepared according to the usual methods decomposes at 185-188;

   [a] D = + 121 (H2O, c = 0.5);
 -the (+) - (-) tartrate - (4S, 5aR) -5-ethyl-4,5,5a, 6-tetrahydro 9,10-dimethoxy-4-methyldibenz [cd, f] indole, [&alpha; ] D20 = -102.4 (H2O, c = 0.5);
 the corresponding hydrochloride prepared according to known methods breaks down at 189-190; [&alpha;] D20 = 122 (H2O, c = 0.5)
Example 8: (#) - (4R *, 5aS *) - 4,5,5a, 6-Tétrahydroxy-4,5-diméthyldibnez [cd, f] -
 indole
 16.8 g (53.8 mM) of (#) - (4R *, 5aS *) - 4.5.5a, 6-tetra-hydro-9,10-dimethoxydibenz [cd, f] indole are dissolved in 400 ml of a 47% aqueous solution of hydrobromic acid and the solution is heated for 3 h at 1300. After evaporation of the mixture, the residue is dissolved in ethanol and the solvent is evaporated.

  After crystallization of the residue in a mixture of methanol and ether, the hydrobromide of the title compound is obtained. The hydrochloride obtained according to known methods decomposes at 185 NMR spectrum 100 MHz (DMSO): 8 1.81 (3H, d, 5Hz, C-4a-CH3).



  Examples 9 to 39:
 By proceeding as described in Example 8 and using the corresponding starting materials, the following compounds of formula Ia are obtained
EMI10.1
 in which R1 and R2 have the meanings given in Table II.



  Table II
EMI10.2


 <tb> <SEP> Decomposition
 <tb> Example <SEP> Rl <SEP> R3 <SEP> Configuration <SEP> [alC
 <tb> <SEP> (H2O, <SEP> c <SEP> = <SEP> 0.5)
 <tb> <SEP> 9 <SEP> CH3 <SEP> CH3 <SEP> (+> (4R *, <SEP> SaR *) <SEP> 185 "'
 <tb> <SEP> 10 <SEP> CH3 <SEP> CH3 <SEP> (-) - (4S. <SEP> 5aR) <SEP> 185 "'
 <tb> <SEP> [a] D <SEP> = <SEP> -97 "
 <tb> <SEP> It <SEP> CH3 <SEP> CH3 <SEP> (+) <4R, <SEP> SaS) <SEP> 185 "'
 <tb> <SEP> [a] D <SEP> = <SEP> +96 "
 <tb> <SEP> 12 <SEP> CH3 <SEP> CH3 <SEP> (+) - (4S, <SEP> SaS) <SEP> 215 '
 <tb> <SEP> [a] 'n <SEP> = <SEP> +136 "
 <tb> <SEP> 13 <SEP> CH3 <SEP> CH3 <SEP> (-> (4R. <SEP> SaR) <SEP> 205 "'
 <tb> <SEP> [a = -135 "
 <tb> <SEP> 14 <SEP> CH3 <SEP> C2H5 <SEP> (-) - (4S, <SEP> 5aR) <SEP>> 280 "2
 <tb> <SEP> [a = <SEP> -65.7 "
 <tb> <SEP> 15 <SEP> CH3 <SEP> C2H, <SEP> (+) - (4R *.

   <SEP> 5aR *) <SEP> 19
 <tb> <SEP> 16 <SEP> CH3 <SEP> C2H1 <SEP> (+) 4R *, <SEP> SaS *) <SEP> 190 "'
 <tb> <SEP> 17 <SEP> CH3 <SEP> n-C3H, <SEP> (+) - (4R * <SEP> SaR *) <SEP> 180 "'
 <tb> <SEP> 18 <SEP> CH3 <SEP> n-C3H7 <SEP> () - (4R *. <SEP> 5aS *) <SEP> 180
 <tb> <SEP> 19 <SEP> CH3 <SEP> iso-C3H7 <SEP> (*> (4R *, <SEP> SaR *) <SEP> 205 "'
 <tb> <SEP> 20 <SEP> CH3 <SEP> iso-C3H, <SEP> (i) - (4R *, SaS *) <SEP> 220 "'
 <tb> <SEP> 21 <SEP> CH3 <SEP> n-C * Hg <SEP> (+> (4R *, <SEP> SaR *) <SEP> 160
 <tb> <SEP> 22 <SEP> CH3 <SEP> n-C4H9 <SEP> (f) - (4R *, <SEP> 5aS *) <SEP> 210 "'
 <tb> <SEP> 23 <SEP> H <SEP> CH3 <SEP> (i) - (SaRS) <SEP> 270-275
 <tb> <SEP> 24 <SEP> H <SEP> C2H3 <SEP> (+> (SaRS) <SEP>> 240 "2
 <tb> <SEP> 25 <SEP> H <SEP> n-C3H, <SEP> (+> (SaRS) <SEP> 258-2600 '
 <tb> <SEP> 26 <SEP> C2H5 <SEP> CH3 <SEP> (+) (4R *, <SEP> SaR *) <SEP>> <SEP> 2
 <tb> <SEP> 27 <SEP> C2H,

    <SEP> CH3 <SEP> (j) <4R *, 5aS *) <SEP>> <SEP> 195 "2
 <tb> <SEP> 28 <SEP> iso-C3H7 <SEP> CH3 <SEP> (+> (4R *, <SEP> SaR *) <SEP>> 225 2
 <tb> <SEP> 29 <SEP> iso-C3H7 <SEP> CH3 <SEP> (i) - (4R *, 5aS <SEP>> 200 "2
 <tb> <SEP> 30 <SEP> n-C3H7 <SEP> CH2 <SEP> (i) - (4R4,5aR4) <SEP>> 215 2
 <tb> <SEP> 31 <SEP> n-C3H7 <SEP> CH3 <SEP> () - (4R *.

   <SEP> 5aS *) <SEP>> 185 2
 <tb> <SEP> 32 <SEP> tert.-C4Hg <SEP> CH3 <SEP> (+) - (4R * <SEP> SaR *) <SEP> 284-285 "2
 <tb> <SEP> 33 <SEP> tert.-C4Hg <SEP> CH3 <SEP> (+) - (4R *, <SEP> 5aS *) <SEP> 270-272 2
 <tb> <SEP> 34 <SEP> sec.-C4Hg <SEP> CH3 <SEP> (f) - (4R *, <SEP> 5aR *) <SEP> 263-265 "2
 <tb> <SEP> 35 <SEP> sec.-C4Hg <SEP> CH3 <SEP> (+) <4R *, <SEP> 5aS +) <SEP> 285-286 "2
 <tb> <SEP> 36 <SEP> n-C4Hg <SEP> CH3 <SEP> (f) - (4R *, <SEP> 5aR *) <SEP> 272 2
 <tb> <SEP> 37 <SEP> n-C4Hg <SEP> CH3 <SEP> (f) - (4Rf, <SEP> 5aS +) <SEP> 269-27le2
 <tb> <SEP> 38 <SEP> -C <SEP> CH,
 <tb> <SEP> 38 <SEP> CH <SEP> \ <SEP> | <SEP> CH3 <SEP> (i) - (4R *, 5aR *) <SEP> l70 2
 <tb> <SEP> CH3
 <tb> <SEP> / CHI
 <tb> <SEP> 39 <SEP> CH <SEP> \ <SEP> -CH / <SEP> CH3 <SEP> (+) - (4R * <SEP> SaS *) <SEP> 258-261'2 <SEP> 2
 <tb> <SEP> CH2
 <tb>
Hydrochloride. êBromhydrate
Example 40:

  : (#) - (4R *, 5aS *) - 9,10-Dibenzoyloxy-4,5,5a, 6-tetrahydro-4,5-dimeth
 yldibenzfcdfjindole
 4.7 ml (40.6 mM) of benzoyl chloride are added to a solution of 1.3 g (4.31 mM) of hydrochloride from (#) - (4R *, 5aS *) - 4,5,5a , 6-tetrahydro-9,10-dimethyldibenz [cd, f] indole in 12 ml of trifluoroacetic acid and the mixture is heated to reflux for 1 h. After evaporation of the reaction mixture, the residue is extracted three times with 100 ml of methylene chloride each time, the combined organic extracts are dried over sodium sulphate and evaporated. The evaporation residue is purified by chromatography on a column of 165 g of silica gel using, as eluent, a mixture of methylene chloride and methanol in the ratio 97: 3.

  The (+) - (4R *, SaS *) 9,10-dibenzoyloxy-4,5,5a, 6-tetrahydro-4,5-dimethyldibenz [cd, f] - indole is thus obtained in the pure state. The hydrochloride melts at 215-225 (with decomposition) after recrystallization from a mixture of ether and acetone.



  100 MHz NMR spectrum (DMSO): 8 1.39 ppm (3H, d, 6Hz, C-4a CH3).



  Examples 41 to 105:
 By proceeding as described in Example 40 and using the appropriate starting materials, the compounds of formula are obtained
EMI11.1
 in which R1, R3 and R "3 have the meanings given in Table III.



  Table III
EMI11.2


 <tb> <SEP> Decomposition
 <tb> <SEP> Example <SEP> R1 <SEP> R2 <SEP> R "3 <SEP> [] 20 <SEP> (c <SEP> = <SEP> 0.5)
 <tb> <SEP> 41 <SEP> H <SEP> -CH3 <SEP> --Cl <SEP> 189-191 1 <SEP> 7
 <tb> <SEP> 42 <SEP> H <SEP> -C2H3 <SEP> -C113 <SEP> 185 "'
 <tb> <SEP> 43 <SEP> H <SEP> -n-C3H7 <SEP> -CH, <SEP> 210 <SEP> 213ol <SEP> 7
 <tb> <SEP> 44 <SEP> H <SEP> -n-C3117 <SEP> -C2H5 <SEP> 210-213 "'
 <tb> <SEP> 45 <SEP> -CH3 <SEP> -C2113 <SEP> -CF3 <SEP> 2l4 <SEP> 219 2 <SEP> 7
 <tb> <SEP> 46 <SEP> -CH3 <SEP> -C2H, -F <SEP> 210-213 2 <SEP> 7
 <tb> <SEP> 47 <SEP> -CH3 <SEP> -C2H5 <SEP> -Br <SEP> 232-239 "2 <SEP> 7
 <tb> <SEP> 48 <SEP> -CH3 <SEP> -C2H5 <SEP> -CH2- <SEP> 196-200 2 <SEP> 7
 <tb> 49 <SEP> - <SEP> CH3 <SEP> - <SEP> C211,

    <SEP> - <SEP> Cl <SEP> 235-238 4
 <tb> <SEP> [a] D <SEP> (MeOH) <SEP> - <SEP> 32.8 "
 <tb> <SEP> 50 <SEP> -CH3 <SEP> C2Hs <SEP> OCl <SEP> 221-223os
 <tb> <SEP> [a] 2D <SEP> (MeOH) <SEP> +28.4 "
 <tb> <SEP> 51 <SEP> -CH3 <SEP> -n-C3H7 <SEP> 158-169 "3 <SEP> 7
 <tb> <SEP> 52 <SEP> -CH3 <SEP> -n-C3H7 <SEP> 7 <SEP> | <SEP> 205-2123
 <tb> <SEP> CH2
 <tb> <SEP> 53 <SEP> -CH3 <SEP> -n-C3H7 <SEP> - (CH2) 3-CH3 <SEP> 155-161 <SEP> 3
 <tb> <SEP> 54 <SEP> -CH3 <SEP> -n-C3H7 <SEP> -C2Hs <SEP> 205-207 3 <SEP> 7
 <tb> <SEP> 55 <SEP> -CH3 <SEP> -C2HsOCH, <SEP> 170-175 2 <SEP> 7
 <tb> <SEP> OCH3
 <tb> <SEP> 56 <SEP> -CH3 <SEP> -C2115 <SEP> - / \ - OCH3 <SEP> 161-163'5 <SEP> 7
 <tb> <SEP> - <SEP> [a] D <SEP> (MeOH) <SEP> + <SEP> 18.8
 <tb> <SEP> OCH3
 <tb> <SEP> 57 <SEP> -CH3 <SEP> -C2113 <SEP> -Cl <SEP> l79t2 <SEP> 7
 <tb>
Table III (continued)
EMI12.1


 <tb> <SEP> Decomposition
 <tb> Example <SEP> R,

    <SEP> R2 <SEP> R / 3 <SEP> [a] D <SEP> (c <SEP> = <SEP> 0.5)
 <tb> <SEP> 58 <SEP> -CH3 <SEP> -C2H, <SEP> ÉÉ <SEP> 188-190 2
 <tb> <SEP> Cl
 <tb> <SEP> 59 <SEP> CH3 <SEP> -C2H, <SEP> 7 <SEP>> <SEP> 188 <SEP> 7
 <tb> <SEP>; É <SEP> [aY0 <SEP> (MeOH) <SEP> -21.2 "
 <tb> <SEP> Cl
 <tb> <SEP> 60 <SEP> -CH3 <SEP> -C2H, <SEP> --OCH3 <SEP> 169-173 "2 <SEP> 7
 <tb> <SEP> 61 <SEP> -CH3 <SEP> -C2H, <SEP> - / \ - OCH3 <SEP> 244-245 "5 <SEP> 7
 <tb> <SEP> [a] D <SEP> (MeOH) <SEP> + <SEP> 26
 <tb> <SEP> 62 <SEP> - <SEP> -CH3 <SEP> -C2H5 <SEP> 198-200 2 <SEP> 7
 <tb> <SEP> OCH3
 <tb> <SEP> 63 <SEP> -CH3 <SEP> -C2H,

    <SEP> CH30C3 <SEP> 203 <SEP> 203-205 "2
 <tb> <SEP> CH3O
 <tb> <SEP> 64 <SEP> -CH3 <SEP> -CH3 <SEP> -CH2- <SEP> 218-223 2
 <tb> <SEP> 65 <SEP> -CH3 <SEP> -CH3 <SEP> 22l 2 <SEP> 7
 <tb> <SEP> 66 <SEP> -CH3 <SEP> -CH3 <SEP> CH \ <SEP> CH / CH2 <SEP> 213 2
 <tb> <SEP> CH2
 <tb> <SEP> 67 <SEP> -CH3 <SEP> -CH3 <SEP> - (CH2) 2-CH3 <SEP> 193-199 2 <SEP> 7
 <tb> <SEP> 68 <SEP> -CH3 <SEP> -CH3 <SEP> -CH3 <SEP> 204 "2
 <tb> <SEP> 69 <SEP> -CH3 <SEP> n-C3H7 <SEP> -iso-C3H7 <SEP> 210 3 <SEP> 7
 <tb> <SEP> 70 <SEP> -CH3 <SEP> -n-C3H7 <SEP> - <SEP> 201-207 2
 <tb> <SEP> 71 <SEP> -CH3 <SEP> -n-C3H7 <SEP> -tert.-C4H0 <SEP> 193-197 2
 <tb> <SEP> 72 <SEP> -CH3 <SEP> -n-C3H7 <SEP> -iso-C3H7 <SEP> 208 2
 <tb> <SEP> 73 <SEP> -CH3 <SEP> -C2H, <SEP> --CH3 <SEP> 205-207 "2 <SEP> 7
 <tb> <SEP> 74 <SEP> -CH3 <SEP> -C2H,

    <SEP> - / \ - CH3 <SEP> 2100S
 <tb> <SEP> - <SEP> [a] ' <SEP> (MeOH) <SEP> + <SEP> 15.4 "
 <tb> <SEP> 75 <SEP> CH3 <SEP> -CH3 <SEP> -C2H, <SEP> 206 <SEP> 206-208 "2 <SEP> 7
 <tb> <SEP> CH3
 <tb> <SEP> 76 <SEP> -CH3 <SEP> -C2H, <SEP> - <SEP> 194-19602
 <tb> <SEP> H3C
 <tb> <SEP> 77 <SEP> -CH3 <SEP> -CH3 <SEP> t3 <SEP> 158-174 3 <SEP> 7
 <tb> <SEP> 78 <SEP> -CH3 <SEP> -CH3 <SEP> -tert.-C4H9 <SEP> 206 2 <SEP> 7
 <tb> <SEP> 79 <SEP> -CH3 <SEP> -CH3 <SEP> -iso-C3H7 <SEP> 194-202o2 <SEP> 2 <SEP> 7
 <tb> <SEP> 80 <SEP> -CH3 <SEP> -CH3 <SEP> 215-235 "67
 <tb> <SEP> [a] D <SEP> (H2O) 56
 <tb> <SEP> 81 <SEP> -CH3 <SEP> -CH3 <SEP> -iso-C3H7 <SEP> 215-225 "6
 <tb> <SEP> [a] a <SEP> (H2O) <SEP> - <SEP> 166
 <tb> <SEP> 82 <SEP> -CH3 <SEP> -C2H,

    <SEP> t9 <SEP> 165-180 "2 <SEP> 7
 <tb>
Table III (continued)
EMI13.1


Decomposition
 <tb> Example <SEP> Rl <SEP> R2 <SEP> R / 3 <SEP> [a] D <SEP> (c <SEP> = <SEP> 0.5)
 <tb> <SEP> 83 <SEP> -CH3 <SEP> -C2Hs <SEP> (3 <SEP> 180-195 3 <SEP> 7
 <tb> <SEP> 84 <SEP> -CH3 <SEP> -C2H, <SEP> 214-221 "57
 <tb> <SEP> [a] D <SEP> (MeOH) <SEP> + <SEP> 12
 <tb> <SEP> 85 <SEP> -CH3 <SEP> -C3H, <SEP> -tert.-C4H0 <SEP> 170-185 2 <SEP> 7
 <tb> <SEP> 86 <SEP> -CH3 <SEP> - <SEP> C2Hs <SEP> -tert.-C4H9 <SEP> 180 "
 <tb> <SEP> [a] 2n '(MeOH) <SEP> -111.2 "
 <tb> <SEP> 87 <SEP> -CH3 <SEP> -C2Hs <SEP> -tert.-C4H0 <SEP> 225-235 3 <SEP> 7
 <tb> <SEP> 88 <SEP> -CH3 <SEP> -C3H5 <SEP> -iso-C3H7 <SEP> 135-150 "2 <SEP> 7
 <tb> <SEP> 89 <SEP> -CH3 <SEP> -C2H, <SEP> -iso-C3H7 <SEP> 220 <SEP> 230o3 <SEP> 7
 <tb> <SEP> 90 <SEP> -CH2 <SEP> -C2H, <SEP> -CH2-OCH3 <SEP> 136-142 "2 <SEP> 7
 <tb> <SEP> 91 <SEP> -CH3 <SEP> -C2H,

    <SEP> -CH2-OCH3 <SEP> 163-171 "
 <tb> <SEP> [a] D <SEP> (MeOH) <SEP> -65.1 "
 <tb> <SEP> 92 <SEP> -CH3 <SEP> -C2H, <SEP> -CH2 <SEP> - <SEP> B <SEP> 136-142 2 <SEP> 7
 <tb> <SEP> CH3
 <tb> <SEP> 93 <SEP> -CH3 <SEP> -C3H, <SEP> -CH2- <SEP> 133-140 2 <SEP> 7
 <tb> <SEP> CH3O
 <tb> <SEP> 94 <SEP> -CH3 <SEP> -C2H5 <SEP> -CH2 <SEP> - <SEP> Cl <SEP> 200-212 2 <SEP> 7
 <tb> <SEP> 95 <SEP> -CH2 <SEP> -C2H, <SEP> -CH3 - / \ - CJ <SEP> 123-133 " <SEP> 7
 <tb> <SEP> [a] 2D0 <SEP> (MeOH) 66.2
 <tb> <SEP> 96 <SEP> -CH3 <SEP> -C2H, <SEP> CH2O <SEP> 199-203 2 <SEP> 7
 <tb> <SEP> Cl
 <tb> <SEP> 97 <SEP> -CH3 <SEP> -C2H, <SEP> -CH3- <SEP> 154-161 2 <SEP> 7
 <tb> <SEP> C1
 <tb> <SEP> 98 <SEP> -CH3 <SEP> -C2H, <SEP> CH2O <SEP> 136-142 6 <SEP> 7
 <tb> <SEP> 98 <SEP> CH, <SEP> (MeOH) <SEP> -CH, - <SEP> L / <SEP> [a] (MeOH) <SEP> -76.3 '
 <tb> <SEP> C1
 <tb> <SEP> 99 <SEP> -CH3 <SEP> -C2H,

    <SEP> CH2 <SEP> 83 <SEP> 239 <SEP> 2440 <SEP> 2 <SEP> 8
 <tb> <SEP> 100 <SEP> -CH3 <SEP> -C2H, <SEP> -CH, <SEP> --C1 <SEP> 187-191 2 <SEP> 8
 <tb> <SEP> CJ
 <tb> <SEP> 101 <SEP> -CH3 <SEP> -C2H, <SEP> -CH3 - Cl <SEP> 210-212 "2 <SEP> 8
 <tb> <SEP> 102 <SEP> -CH3 <SEP> -C2H, <SEP> QCI <SEP> 199 <SEP> 2I4O2 <SEP> 7
 <tb> <SEP> 103 <SEP> -CH2 <SEP> -C2H5 <SEP> < <SEP> 184-189 2 <SEP> 7
 <tb> <SEP> F
 <tb>
Table III (continued)
EMI14.1


 <tb> <SEP> Example <SEP> R1 <SEP> R2 <SEP> R "3 <SEP> Decomposition
 <tb> a] D <SEP> R1 <SEP> R2 <SEP> Rw3 <SEP> [a] D <SEP> (c <SEP> = <SEP> 0.5)
 <tb> <SEP> 104 <SEP> -CH3 <SEP> -C2115 <SEP> / <SEP> 184-190 2 <SEP> 7
 <tb> <SEP> F
 <tb> <SEP> 105 <SEP> -CH3 <SEP> -CH3 <SEP> -C112 / <SEP> 208-210 6 <SEP> 7
 <tb> <SEP> [a] D <SEP> (MeOH) <SEP> -72.7 "
 <tb> t (+) - (SaRS). a (+) - (4S, SaR).



  2 (+) - (4R *, SaS *). 6 (-) - (4S, SaR).



  3 (+ -) - (4R *, SaR *). 7 Hydrochloride.



  4 (-) - (4R, 5aS). 8 Methanesulfonate.



   The compounds of the invention, in particular the compounds of formula I, and their salts have not been described until now in the literature. In tests carried out on laboratory animals, they stand out for their interesting pharmacodynamic properties.



  They exert in particular a stimulation of the central dopaminergic receptors, as appears from the following tests.



   The action of the compounds of formula I on the central dopaminergic receptors was studied in rats according to the method described by U. Ungerstedt in Acta Physiol-Scand. , suppl. 367, 69-93 (1971). 6-hydroxydopamine is injected unilaterally into the substantia nigra, which leads, after a week, to unilateral degeneration of the nigro-striated pathways. This unilateral lesion generates hypersensitivity of the striated dopaminergic receptors which results, after administration of a stimulating substance, by a behavior of contralateral rotations to the lesion. Administered intraperitoneally at doses of between approximately 0.03 and 30 mg / kg, the compounds of the invention induce, in this test, a marked stimulation of the central dopaminergic receptors.



   The action of the compounds of the invention on the central dopaminergic receptors has also been demonstrated by studying the behavior of the rat. Stimulation of dopaminergic receptors gives rise to stereotypical behavioral symptoms in rats such as:
 I) intermittent sniffles,
 2) persistent sniffing, occasional licking,
 3) licking, occasional bites,
 4) intense and persistent bites.



   Rats weighing from 180 to 220 g are placed in an observation cylinder 30 cm in diameter. After 30 min necessary for the animal to acclimatize to its environment, it is administered the test substance intraperitoneally. The behavior of the rat is studied for a total duration of 7 h, as follows: observations are carried out for 2 min at 30 min intervals for the first two hours, then at 60 min intervals for the five following hours. The degree of stereotypy is determined by proceeding according to the method described by Costall,
Naylor and Olley [Euro. J.

  Pharmac. , 18, 83-94 (1972)]. Administered intraperitoneally at doses of between 0.03 and 30 mg / kg, the compounds of the invention induce a marked stimulation of the central dopaminergic receptors, resulting, in this test, in a manifestation of sniffles, licks and bites as described above.



   Thanks to this property, the compounds of the invention and their salts can be used in therapy as an agent for the stimulation of central dopaminergic receptors, for example for the treatment of Parkinson's disease. They will be prescribed in daily doses of between approximately 0.5 and 100 mg, which will be administered at once or in several unit doses, each containing approximately 0.1 to 50 mg of active substance, at a rate of 2 to 4 times a day or in late form.



   The compounds of the invention and their pharmaceutically acceptable salts do not exhibit significant side effects.



   The compounds of the invention can be administered both in the form of free bases and in the form of their acid addition salts, the activity of which is of the same order as that of the corresponding free bases.



   The compounds of the invention, in particular the compounds of formula I, as well as their pharmaceutically acceptable salts can be used as medicaments either alone or in the form of pharmaceutical compositions suitable for administration by the oral, rectal or parenteral route . To prepare suitable pharmaceutical forms, the active substance is worked with pharmacologically inert mineral or organic excipients. We can use for example: for tablets and dragees: lactose, starch, talc, stearic acid, etc .; for syrups: water, sucrose, invert sugar, glucose, etc .; for injectable preparations: water, alcohols, glycerol, vegetable oils, etc .; for suppositories: natural or hardened oils, waxes, fats, etc.

 

   The preparations may also contain suitable preservatives, dissolving agents, stabilizers, wetting agents, sweeteners, colors, flavorings, etc.



  Example of pharmaceutical composition: tablets
 Compound of Example 50 21.4 mg *
 Magnesium stearate 1 mg
 Polyvinylpyrrolidone 4 mg
 Talc 8 mg
 Corn starch 10 mg
 Lactose 152.1 mg
 Dimethyl silicone oil 0.5 mg
 Polyethylene glycol 6000 3 mg
 For one tablet weighing 200.0 mg
 * Corresponds to 20 mg of compound in free base form.



   The active substance, magnesium stearate, polyethylene glycol 6000, polyvinylpyrrolidone, talc, starch and lactose are dry mixed. The mixture thus obtained is granulated with dimethylsilicone oil suspended in water, dried and the crushed granule is compressed to make tablets.


    

Claims (22)

 CLAIMS  1. 4,5, Sa, 6-Tetrahydrodibenz [cd, tlindole comprising, in one or both of the condensed benzene rings, at least one oxy substituent chosen from hydroxy, acyloxy and ether groups, At least one of these oxy substituents being a hydroxy or acyloxy group when the molecule is unsubstituted in position 4, and the acid addition salts of this compound.  2. 4,5,5a, 6-Tetrahydrodibenz [cd, ffindole according to claim 1, characterized in that it comprises two substituents oxy.  3. 4,5,5a, 6-Tetrahydrodibenz [cd, flindole according to claim 2, characterized in that the two oxy substituents are located in positions 9 and 10 of the molecule.  4. 4,5,5a, 6-Tetrahydrodibenz [cd, flindole according to one of claims 1 to 3, characterized in that the oxy substituent (s) are chosen from hydroxy and acyloxy groups.  5. 4,5,5a, 6-Tetrahydrodibenz [cd, flindole according to claim 4, characterized in that it corresponds to formula (I) EMI1.1  in which    R1 represents a hydrogen atom, an alkyl group containing from 1 to 10 carbon atoms, a cycloalkyl group containing from 3 to 7 carbon atoms or a cycloalkylalkyl group in which the cycloalkyl residue contains from 3 to 7 carbon atoms and the alkyl residue contains from 1 to 4 carbon atoms,  R2 represents an alkyl group containing from 1 to 5 carbon atoms, and  the substituents R3 are identical and represent a hydroxy or acyloxy group.  6. 4,5,5a, 6-Tetrahydrodibenz [cd, flindole according to claim 5, characterized in that the acyloxy groups correspond to the formula R, - CO - O-, in which R represents an optionally substituted alkyl group, a cycloalkyl group containing from 3 to 7 carbon atoms, an unsubstituted or substituted phenyl residue, or a 5 or 6-membered heterocycle.  7. 4,5,5a, 6-Tetrahydrodibenz [cd, flindole according to claim 6, characterized in that  i) the optionally substituted alkyl group represents an unsubstituted alkyl group containing from 1 to 17 carbon atoms, an alkyl group containing from 1 to 4 carbon atoms monosubstituted by a cycloalkyl group containing from 3 to 7 carbon atoms, or a group alkyl containing from 1 to 5 carbon atoms monosubstituted by a halogen atom, by a hydroxy, amino, carboxy, phenoxy, I-pyrrolidinyl, piperidino, morpholino, alkoxy group containing from I to 4 carbon atoms, alkylthio containing from 1 with 4 carbon atoms, alkylamino containing from I to 4 carbon atoms or dialkylamino in which the alkyl radicals each contain from I to 4 carbon atoms,  by a phenyl group optionally carrying 1, 2 or 3 substituents chosen from halogen atoms and trifluoromethyl groups, alkyl containing from 1 to 4 carbon atoms, alkoxy containing from 1 to 4 carbon atoms, alkylthio containing from 1 to 4 carbon atoms and dialkylamino in which the alkyl radicals each contain from I to 4 carbon atoms, or by a phenyl group substituted by a methylenedioxy group,  ii) the phenyl residue is a phenyl group optionally carrying 1, 2 or 3 substituents chosen from halogen atoms and trifluoromethyl groups, alkyl containing from 1 to 4 carbon atoms, alkoxy containing from 1 to 4 carbon atoms, alkylthio containing from 1 to 4 carbon atoms and dialkylamino in which the alkyl radicals each contain from 1 to 4 carbon atoms, or a methylenedioxyphenyl group,  and  iii) the 5 or 6-membered heterocycle has only one heteroatom chosen from oxygen, sulfur or nitrogen.  8. 4,5,5a, 6-Tetrahydrodibenz [cd, flindole according to claim 7, characterized in that the monosubstituted alkyl group represents an alkyl group monosubstituted by a halogen atom, by a phenoxy group, by an alkoxy group containing from 1 to 4 carbon atoms, by an alkylthio group containing from 1 to 4 carbon atoms, by a dialkylamino group in which the alkyl radicals each contain from 1 to 4 carbon atoms, by a cycloalkyl group containing from 3 to 7 atoms carbon, or by a phenyl group optionally carrying 1, 2 or 3 substituents chosen from halogen atoms and alkyl groups containing from 1 to 4 carbon atoms, alkoxy containing from 1 to 4 carbon atoms and alkylthio containing from 1 to 4 carbon atoms.  9. 4,5,5a, 6-Tetrahydrodibenz [cd, flindole according to claim 5, characterized in that it corresponds to formula (Ia) EMI1.2  in which R1 and R2 have the meanings given in claim 5.  10. 4,5,5a, 6-Tetrahydrodibenz [cd, ffindole according to claim 5, characterized in that it corresponds to the formula (Ib) EMI1.3  in which the symbols R'3 each represent a residue R, - CO - O - as specified in one of claims 6 to 8, and R1 and R2 have the meanings given in claim 5.    11. 4,5,5a, 6-Tetrahydrodibenz [cd, flindole according to claim 10, characterized in that it is 4,5,5a, 6-tetrahydro-9,10-di (p-chlorobenzoyloxy) -5-ethyl-4-methyldibenz [cdaflindole.  12. 4,5,5a, 6-Tetrahydrodibenz [cd, findole according to claim 10, characterized in that it is 4,5,5a, 6-tetrahydro-9,10-di (phenylacetyloxy) -4 , 5-dimethyldibenz [cd, flindole.  13. 4,5,5a, 6-Tetrahydrodibenz [cd, findole according to claim 1, characterized in that the oxy substituent (s) are ether groups.  14. 4,5,5a, 6-Tetrahydrodibenz [cd, flindole according to claim 13, characterized in that it comprises at least one ether group in one or both of the condensed benzene rings, the compound being substituted in position 4 of the molecule.    15. 4,5,5a, 6-Tetrahydrodibenz [cd, flindole according to claim 14, characterized in that it corresponds to formula (II) EMI1.4  in which  the symbols Z each represent an arylalkoxy or alkoxy group containing up to 10 carbon atoms,    R1 represents an alkyl group containing from 1 to 10 carbon atoms, a cycloalkyl group containing from 3 to 7 carbon atoms or a cycloalkylalkyl group in which the cycloalkyl residue contains from 3 to 7 carbon atoms and the alkyl residue contains from 1 to 4 carbon atoms, and  R2 represents an alkyl group containing from 1 to 5 carbon atoms.  16. 4,5,5a, 6-Tétrahydrodibenz [cd, ffindole, characterized in that it corresponds to formula (II ')   EMI2.1  in which  the symbols Z each represent an arylalkoxy or alkoxy group containing up to 10 carbon atoms,    R'l represents a hydrogen atom, and  R2 represents an alkyl group containing from 1 to 5 carbon atoms.  17. 4,5,5a, 6-Tetrahydrodibenz [cd, faindole according to one of claims 13 to 16, characterized in that the ether group is a methoxy group.  18. 4,5,5a, 6-Tetrahydrodibenz [cd, flindole according to one of claims 1 to 17, characterized in that it is in the form of an optically active isomer.  19. A 4,5,5a, 6-tetrahydrodibenz [cd, ffindole according to claim 1, characterized in that it is chosen from (+) - (4R, SaS) - 4,5,5a, 6-tetrahydro -9.1 0-dihydroxy-4,5-dimethyldibenz [cd, fzindole, le (-) - (4S, 5aR) -4,5,5a, 6-tétrahydro-9, 1 0-dihydroxy-4,5- dimethyldi benz [cd, flindole, le (+) - (4S-5aS) -4,5,5a, 6-tétrahydro-9, 1 0-dihydr- oxy-4,5-diméthyldibenz [cd, faindole, le (- ) - (4R, 5aR) -4,5,5a, 6-tetra-hydro-9, 1 0-dihydroxy-4,5-dimethyldibenz [cd, f] indole, the (-) - (4S, 5aR) - 5-ethyl-4,5,5a, 6-tetrahydro-9, O-dihydroxy-4-methyldi- benz [cd, f] indole, le (-) - (4R, 5aS) -9, 1 0-di- (p-chlorobenzoyloxy) -5 ethyl-4,5,5a, 6-tetrahydro-4-methyldibenz [cd, f] indole,  (+) - (4S, 5aR) -9,10-di- (3,4-dimethoxybenzoloxy) -5-ethyl-4,5,5a, 6-tetra hydro-4-methyldibenz [cd, f] indole, le (-) - (4S, 5aR) -9, 1 0-di- (o chlorobenzoyloxy) -5-ethyl-4,5,5a, 6-tétrahydro-4-méthyldi- benz [cd, flindole, le (+ ) - (4S, 5aR) -9, 1 0-di- (p-methoxybenzoyloxy) -5-ethyl-4,5,5a, 6-tetrahydro-4-methyldibenz [cd, f] indole, the (+ ) (4S, 5aR) -9, 1 0-di- (p-methylbenzoyloxy) -5-ethyl-4,5,5a, 6-tétra- hydro-4-méthyldibenz [cd, flindole, le (-) - ( 4S, 5aR) -9, 10-dibenzoyl-oxy-4,5,5a, 6-tetrahydro-4,5-dimethyldibenz [cd, f] indole, le (- (4S, SaR) -9, 1 0-diisobutyryloxy -4,5,5a, 6-tetrahydro-4,5-dimethyldi- benz [cd, flindole, le (+) - (4S, 5aR) -9,  1 0-dibenzoyloxy-5-ethyl- 4,5,5a, 6-tetrahydro-4-methyldibenz [cd, f] indole, the (-) - (4S, 5aR) -5ethyl-4,5,5a, 6- tetrahydro-4-methyl-9, 1 0-dipivaloyloxydibenz [cd, ffindole, le () - (4S, 5aR) -9,10-di- (p-methoxyphenylacetyloxy) -5- ethyl-4,5,5a, 6 -tetrahydro-4-methyldibenz [cd, ndole, le (- (4S, 5aR) -9,10-di- (p-chlorophenylacetyloxy) -5-ethyl-4,5,5a, 6-tetra hydro-4-methyldibenz [cd, flindole, (-) - (4S, 5aR) -9, 1 0-di- (ochlorophenylacetyloxy) -5-ethyl-4,5,5a, 6-tetrahydro-4-methyldibenz [cd, f] indole and (-) - (4S, 5aR) -4,5,5a, 6-tetrahydro-4,5-dimethyl 9,10-di (phenylacetyloxy) dibenz [cd, flindole.  20. 4,5,5a, 6-Tetrahydrodibenz [cd, f] indole according to claim 1, characterized in that it is (+) - (4S, 5aR) -9,10-di- (p chlorobenzoyloxy) -5-ethyl-4,5,5a, 6-tetrahydro-4-methyldi-benz [cd, flindole.  21. 4,5,5a, 6-Tetrahydrodibenz [cd, flindole according to one of claims 1 to 20, characterized in that it is in the form of an acid addition salt.  22. Medicinal product, characterized in that it contains, as active principle, alone or in combination with pharmaceutically acceptable excipients and vehicles, a 4,5,5a, 6-tetrahydrodi benz [cd, fXindole specified to one of claims 1 to 14 and 19 or 20, in the free base state or in the form of a pharmaceutically acceptable acid addition salt.  The subject of the present invention is new phenanthrene derivatives and the drugs containing these compounds.  The invention relates to phenanthrene derivatives, in this case 4,5,5a, 6-tetrahydrodibenz [cd, flindoles having, in one or both of the condensed benzene rings, at least one oxy substituent chosen from hydroxy, acyloxy and ether groups, at least one of these oxy substituents being a hydroxy or acyloxy group when the molecule is unsubstituted in position 4.  The oxy substituent (s) may for example be a hydroxy group or a group capable of being hydrolyzed under physiological conditions into a hydroxy group, for example an acyloxy group. It can also be an ether group. Advantageously, position 4 is substituted, for example by a cycloalkyl or alkyl group.  The compounds of the invention advantageously contain up to 4 oxy substituents, preferably 2 oxy substituents. The oxy substituents are advantageously found in positions 9 and / or 10.  More particularly, the invention relates to the compounds of formula I EMI2.2  in which    R1 represents a hydrogen atom, an alkyl group containing from I to 10 carbon atoms, a cycloalkyl group containing from 3 to 7 carbon atoms or a cycloalkylalkyl group in which the cycloalkyl radical contains from 3 to 7 carbon atoms and the alkyl residue contains from I to 4 carbon atoms.  R2 represents an alkyl group containing from 1 to 5 carbon atoms, and  the substituents R3 are identical and represent a hydroxy or acyloxy group.    R1 preferably represents an alkyl group. When R1 represents an alkyl group, the latter advantageously contains from 1 to 6 carbon atoms and can signify, for example, the methyl group.  R2 advantageously signifies an alkyl group containing from 1 to 4 carbon atoms, preferably from 1 to 3 carbon atoms.  The substituents R3 preferably represent an acyloxy group. These groups can correspond to the formula Ra - CO - O -, in which Ra represents an optionally substituted alkyl group, a cycloalkyl group containing from 3 to 7 carbon atoms, a phenyl residue or a 5 or 6 membered heterocycle.  When Ra represents an alkyl group, the latter may advantageously contain from 1 to 17 carbon atoms, preferably from 1 to 7 carbon atoms, and may be straight or branched chain.  Ra can represent a substituted alkyl group, the alkyl chain of which advantageously contains from 1 to 5 carbon atoms. It is advantageously a monosubstituted alkyl group. Examples of substituents that may be mentioned are halogens, a phenyl residue and carboxy, hydroxy, amino, alkylamino groups containing from 1 to 4 carbon atoms, alkoxy containing from 1 to 4 carbon atoms, dialkylamino in which the alkyl radicals each contain from 1 to 4 carbon atoms, alkylthio containing from 1 to 4 carbon atoms, phenoxy, I-pyrrolidinyl, piperidino or morpholino; advantageously, the substituent is a phenyl residue. R, can also represent an alkyl group containing from 1 to 4 carbon atoms and substituted by a cycloalkyl group containing from 3 to 7 carbon atoms.    When Ra represents a phenyl radical or an alkyl group substituted by a phenyl radical, the phenyl radical in question may be an unsubstituted phenyl group, a phenyl group substituted by 1, 2, or 3 identical or different substituents chosen from atoms halogen and trifluoromethyl groups, alkyl containing from 1 to 4 carbon atoms, alkoxy containing from 1 to 4 carbon atoms, alkylthio containing from 1 to 4 carbon atoms and dialkylamino in which the alkyl radicals each contain from I to 4 carbon atoms , or ** ATTENTION ** end of the CLMS field may contain start of DESC **.