SE434048B - DERIVATIVES OF 4,5,5A, 6-TETRAHYDRO-DIBENS (CD, F) INDOL, SET TO MAKE THESE AND PHARMACEUTICAL COMPOSITIONS CONTAINING THESE - Google Patents

Description

R 1 is hydrogen, (C 1-10) alkyl, (C 3-7) cycloall R 2 is (C 1-5) alkyl, and the R 3 substituents are the same and are hydroxy or acyloxy groups.

R 1 is preferably an alkyl group. When R 1 is an alkyl group, it suitably contains 1-6 carbon atoms and may, for example, represent methyl.

R 2 is suitably an alkyl group containing 1 to 11 carbon atoms, preferably 1-3 carbon atoms.

The R 3 substituents are preferably acyloxyl groups. These may be groups of the formula R -co-o- B where Ra is unsubstituted or substituted alkyl, (C 3-7) cycloalkyl, a phenyl group or a 5- or S-free heterocyclic ring. When Ra is an alkyl group, it suitably contains 1-7 carbon atoms, preferably 1-7 carbon atoms, and it may be straight-chain or branched.

Ra may be a substituted alkyl group, which in the alkyl chain suitably contains 1-S carbon atoms. It is suitably a monosubstituted alkyl group. Examples of substituents which may be mentioned are carboxy, hydroxy, amino, (C 1-4 alkylamino, (C 1-4) alkoxy, di- (C 1-4) alkylamino, halogen, (C 1-4) alkylthio, phenoxy, an phenyl group, 1-pyrrolidinyl, piperidino or morpholino, but it is suitably a phenyl group Ra may also be, for example, an alkyl group which in the alkyl chain contains 1 to 1 + carbon atoms and is substituted by (C 3-7) cycloalkyl.

When Ra is a phenyl group or alkyl substituted with a phenyl group, the phenyl group may be unsubstituted or contain, 2 or 3 identical or different substituents, selected for example from halogen, trifluoromethyl, (C 1-6 alkyl, (C 1-4) alkoxy, (C 1-6 alkylthio and di- (C 1-6 alkylamino)) , or a methylenedioxy group.

The phenyl group ring is preferably mono- or disubstituted.

When Ra is an alkyl group substituted with a phenyl group, Ra is preferably a benzyl group. The phenyl ring may have substituents selected, for example, from halogen, (C 1 -C 4) alkyl, (C 1 -C 4) alkoxy or (C 1 -C 4) alkylthio.

When R a is a heterocyclic ring, it is suitably a heterocycle which contains oxygen, nitrogen or sulfur as the only heteroatom, e.g. pyridine, thiophene or furan.

RE; is preferably (C 1-7) alkyl, (C 3-6) cycloalkyl, unsubstituted phenyl, phenyl which is mono- or disubstituted by chlorine, fluorine, trifluoromethyl, (C 1-8) alkyl or (C 1-4) alkoxy, unsubstituted benzyl, or benzyl which is mono- or disubstituted with chlorine, íluoro, (C 1-6 alkyl or (C 1-6 alkoxy)).

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

Representative groups of the compounds are those of formula I 'OH g Ho U / "la _ I' Rz 'where R 2 has the meaning given above, and formula 1" III where R 2 has the meaning given above and the R'a substituents are identical and are unsubstituted or substituted (C 1-17) alkyl, (C 3-7) cycloalkyl, a phenyl group or a 5- or 6-membered heterocyclic ring.

R 2 is suitably (C 1-4) alkyl, R'a is suitably (C 1-4) alkyl, (C 34) -cycloalkyl, (C 3-7) cycloalkyl (C 1-2) alkyl, phenyl, phenyl monosubstituted with chlorine or methoxy, or benzyl.

The compounds according to the invention can be prepared in a manner known per se.

For example, a 4,5,5a, 6-tetrahydro-dibenz [cd] -indole, which contains at least one hydroxy or acyloxy substituent in one or both of the fused benzene rings, can be prepared by a process which comprises a) provides a compound containing at least one hydroxy substituent in one or both of the fused benzene rings by cleaving the ether group or groups in a corresponding compound containing at least one leaving group ether in one or both of the fused benzene rings, or b) preparing 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 substituent in one or both of the fused benzene rings. More particularly, the invention relates to a process for the preparation of compounds of formula I, in which a) a compound of formula Ia Ia is formed wherein R 1 and R 2 have the meaning given above, by cleaving the ether groups Z in a compound of formula ll i where R 1 and R 2 have the meaning given above and Z is a leaving group which can be cleaved off, or r 10 b) - represents a compound of the formula Ib Ib where R 1 and R 2 have the meaning given above and the groups PO 3 are identical acyloxy groups, by acylating a compound of formula Ia. The ether cleavage method according to the invention, in particular the process a) can be carried out in a conventional manner for cleavage of ether groups. For example, the reaction can be carried out by treating the starting materials with a strong mineral acid, e.g. hydrobromic acid or hydroiodic acid, at a temperature of at least 100 ° C, preferably from 100 ° C to the boiling point of the reaction mixture, especially at 130 ° C. The ether group or groups, especially the groups Z, are preferably arylalkoxy or alkoxy, which contains up to 10 carbon atoms, especially a benzyloxy, ethoxy or methoxy group, preferably a methoxy group.

The acylation method according to the invention, in particular process b), can be carried out in a conventional manner for the selective acylation of phenolic groups in the presence of an amine function. For example, an acylating agent can be used as a functional derivative of an acid such as an acid chloride, acid bromide or acid anhydride.

The reaction is conveniently 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, which contain 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 according to the invention , can be prepared by a process c), which comprises reducing the Saß double bond in a corresponding 11-dihydro-dibenz [cd, f] indole, which is correspondingly substituted or is oxo-substituted in the III position when it is desired to prepare a compound , which is unsubstituted in the ll position.

In particular, the compounds of formula II can be prepared by reduction of the 5a, 6-double bond and, when present, the II-oxo group, in a compound of formula III III where R 2 and the groups Z have the meaning given above, and either X is hydrogen and Y is the same as R 1, or X and Y together are oxo.

The reduction may conveniently be carried out by means of methods conventionally used for the reduction of enamines or imines, for example with zinc in an aqueous mineral acid, preferably hydrochloric acid, optionally in the presence of a mercury (II) salt, for example mercury (II) chloride. The reaction may conveniently be carried out in an organic solvent, e.g. a lower alkanol, for example ethanol, and at temperatures from 50 ° C to the boiling point of the reaction mixture. Under these conditions, any dioxo group present may be reduced at the same time.

The resulting compounds of the invention can be isolated from the reaction mixture and purified in a known manner. The free base forms can be converted to acid addition salts in a conventional manner, and vice versa. Suitable acids for salt formation are hydrochloric acid, hydrobromic acid and methanesulfonic acid.

The compounds according to the invention have an asymmetric carbon atom in the 5a position and can be obtained as a racemate or as one of the optically active forms, i.e. as a single enantiomer. When the nucleus is substituted in the β-position, especially when R 1 in formula I has a meaning other than hydrogen, the compounds according to the invention have two asymmetric carbon atoms in the 4- and 5a-positions, so that two racemates can occur. Based on optically active starting materials, optically active end products can be obtained. Racemic starting materials give racemic end products. The individual racemates can be divided into the enantiomers by known methods, e.g. by fractional crystallization of diastereoisomeric salts, e.g. their salts with (+) - or (J-tartaric acid or di-p-toluoyl-ß- or d-tartaric acid.

The cleavage of the racemates can be carried out after the final step in the synthesis or possibly in an earlier step. The summer separation is preferably carried out before the cleavage of the ether groups.

The starting materials of process c), which are monosubstituted in the 4-position, especially compounds of formula III, where X is hydrogen and Y has a meaning other than hydrogen, have an asymmetric carbon atom in the β-position. When reducing these compounds, a second asymmetric carbon atom in Sa position.

Compounds of formula IIIa IIIa wherein R 2 and the groups Z have the meaning given above, can be prepared, for example, according to the following reaction scheme: 10 7905282-s II Ia \ lil-COO-Alk R 2 VIII In the reaction scheme, the groups Z and R 2 have the same meaning as above, R '2 is hydrogen or (C 1-4) all The reactions can be carried out in a conventional 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, followed by basic hydrolysis. Acylation of compounds of formula V can be carried out, for example, with a compound of formula R "2-CO-Hal, where Hal has the meaning given above and R" 2 is (C Hpalkyl, in the presence of an acid acceptor, e.g. N- Ethyl diisopropylamine When R'2 reacts with formic acid in the presence of NN-carbonyldiimidazole. The compounds with are hydrogen, the reaction can be carried out by a compound of formula V having formula VI can be reduced, for example, with diborane. The compounds of formula VIII may conveniently be prepared by reacting the compound of formula VI with a chloroformate in an organic solvent and in the presence of an acid acceptor, eg N-ethyldiisopropylamine Treatment of compounds of formula VIII with, for example, an alkyl or aryl lithium compound , preferably n-butyllithium or: c-butyllithium in tetrahydrouran / hexane at temperatures from -10 ° C to 0 ° C, give compounds of formula IIIa.

The other 11-oxo-substituted starting materials in process c) can be prepared in an analogous manner.

Compounds of formula IIIb IIIb wherein the groups Z and R 1 and R 2 have the meaning given above can be prepared, for example, according to the following reaction scheme, wherein the groups Z, R I, R 2 and Hal have the meaning given above and Ane is an anion: g __; nïb 10 15 20 25 7905282-5 The reactions can be carried out according to known methods.

The acylation of the compounds of formula V can take place, for example, by reaction with a compound of the formula Hal-CO-R1, where R1 is the same as R1, except that it can not represent hydrogen, and Hal has the meaning given above, in the presence of an acid acceptor, e.g. N-ethyldiisopropylamine. When R 1 is 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 may conveniently be alkylated with an alkyl iodide under the conditions of a phase transfer catalyst reaction, for example in the presence of tetrabutylammonium hydrogen sulphate. Treatment of compounds of formula X with, for example, n-butyllithium or git: butyllithium in tetrahydrofuran / hexane at temperatures from -10 ° C to 0 ° C gives the compounds of formula XI. The dehydration of the compounds of formula X1 can be carried out, for example, with a mineral acid, for example hydrochloric acid in ethereal solution. The salts of formula X11 can be reduced to compounds IIIb with sodium borohydride in tetrahydrofuran.

The starting materials of formula X can also be prepared in a conventional manner the compounds of formula VII by acylation with compounds of formula R I-CO-Hal as described above.

The compounds of formula X1, wherein R1 is R1 as defined above, may also be prepared in a conventional manner from compounds of formula III by reaction with compounds of formula R1 to Li, wherein R1 has the meaning given above. Compounds of formula XI, wherein R 1 is hydrogen, may also be prepared in a conventional manner from compounds of formula IIIa by reduction with LiAlHw Compounds of formula IIIb, in which R 1 is methyl, may also be prepared according to the following reaction scheme, wherein groups Z and R 2 have the meaning given above, Hap is chloride, bromide or iodide, An is chloride, bromide, iodide, CHB-SO49 or CH SO46, and either Rx is hydrogen and Ry is bromomethyl or Rx and R together are: CH: y 2 10 l5 7905282-5 10 years 3 XIII - XIV \ / Z z Rx / æ Ry \ ---- u-ca3 <å fl ale 2 xvI lv tube (where RI ärci-i3) The alkylation of compounds of formula XIII can take place, for example, by reaction with compounds of the formula An-R 2, wherein R 2 has the meaning given above and An is chlorine, bromine or iodine, or when R 2 is methyl or ethyl, with dimethyl or diethyl sulphate. The ring opening of the compounds of formula XIV can be carried out in a conventional manner with an alkali metal alcoholate, preferably potassium tert-butylate 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 can take place under oxidative conditions, for example with bromine or a halogenating compound, for example N-bromosuccinimide. The regioselective cyclounctionalization of XV to XVI with bromine can be carried out at temperatures from -OOC to 50 ° C, preferably at room temperature, suitably in an inert organic solvent, for example a halogenated hydrocarbon, e.g. methylene chloride, chloroform or carbon tetrachloride, preferably chloroform. The reaction with N-bromosuccinimide may conveniently be carried out at temperatures from 0 ° C to 5 ° 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 resulting quaternary compounds of formula XVI, followed by rearrangement, is suitably carried out at temperatures higher than BOOC, preferably between 80 ° C and 100 ° C, especially at 100 ° C, in an organic solvent, e.g. benzene, dimethylformamide or ethanolamine, preferably ethanolamine.

The remaining starting materials for process c), where the III position is unsubstituted or substituted, are prepared in a manner analogous to that described above for compounds IIIb. an R1 substituent other than hydrogen, the products of the above reactions can be isolated and purified in a known manner. To the extent that the preparation of any particular starting material is not specifically described, this may be done in a conventional or analogous manner.

It may be noted that some of the above compounds may be in optically active forms.

Some of the starting materials are new and are particularly useful intermediates for the preparation of pharmacologically active compounds, and they form part of the invention.

Thus, the following compounds are valuable intermediates thanks to the functional groups present, e.g. ether groups, ketone groups, double bonds in the Sa-é positions: a) 11,5,5a, 6-tetrahydro-dibenz [cd fi] indoles with at least one ether group on one of the fused benzene rings, with the proviso that when more than one ether group the groups are bonded to the same fused benzene ring, b) 4,5-dihydro-dibenz [cd, f] indoles having at least one hydrogen bonded to the carbon atom in the lit position and with at least one leaving group ether in any of the positions 1-3 and 7-10, c) lk fi-dihydro-ß-oxo-dibenz [cdi] indoles with only one or two cleavable groups in any of positions 7-10 and without any additional oxy substituents in the core.

In particular compounds of the formula IIl'a 7905282-5 12 -Rz ü! III'a where R 2 has the meaning given above, wherein the ring B has only one or two cleavable ether groups and no further oxy substituent is present in the core, compounds of formula III 'b R 5 g ü l 111m. wherein R 1 and R 2 have the meaning given above and the ring A and / or B contain at least one leaving group which can be cleaved off, and compounds of the formula V 'wherein Hal has the meaning given above and the ring A and / or B contain at least one leaving group (2). of which the compounds IIIa, IIIb and V are examples), are due to the functional groups present, especially the ether and amino groups and the halogen atom, valuable intermediates for the preparation of a variety of different compounds. In the above-mentioned intermediates there are suitably two ether groups, e.g. in 9- and IO position. The ether group or groups are suitably (C 1-6 alkoxy).

In the following examples, all temperatures are given in degrees Celsius and are uncorrected. 10 15 20 25 30 35 79052824; The absolute configuration of the optically active compounds of formula II, corresponding to Example 7 and in which Z is methoxy and R 1 and R 2 are methyl, was determined by X-ray analysis. The absolute configuration of the other optically active compounds of formula II was determined by analogy on the basis of their optical rotation. It is believed that the compounds of formula I prepared from the corresponding compounds of formula II have the same absolute configuration.

Example 1 taaSi-szeaie-eifahwifa-zaeamagxi-z-msosdenslgdiflißei (compound of formula II) 544 ml (0.06M) of a 3% aqueous solution of mercury (II) chloride was added under nitrogen atmosphere and stirring to 272 g (1 + 1,7M) zinc stoite and the mixture was stirred for 5 minutes at room temperature. A suspension of 40 g (0.3l16M) of 4,5-dihydro-9,10-dimethoxy-5-methyl-1-oxo-dibenz [cd, f] indole in 5140 ml of ethanol was added, as well as 3400 ml of 2N hydrochloric acid. The reaction mixture was heated to 650 and kept at this temperature for 30 minutes. After adding 272 ml of 3796 g of hydrochloric acid, the reaction mixture was stirred for 16 hours at 5 ° C. after cooling now the 100 ° filter-idea suspension. The filtered zinc dust was washed with a 1600 ml mixture of methylene chloride and ethanol. The filtrate was cooled in an ice bath, made alkaline with 1 liter of concentrated NH 4 Olrl and extracted three times with methylene chloride (2000 ml each time). The combined organic phases were dried, filtered and evaporated to give (SaRS) -1, 5,5a, 6-tetrahydro-9,10-dimethoxy-fi-methyl-dibenz- [cd fl-indole (m.p. 126-128 ° with decomposition after crystallization from ether).

NMR 10 MHz (δ C, δ 2.66 ppm (3H, s, N-c_r_i3), 4.25 (1H, d, 11Hz, c-u «i1).

The starting material can be prepared as follows: a) A mixture of 860 ml (6.16M) of trifluoroacetic anhydride and 860 ml (11, 24M) of trifluoroacetic acid is added at room temperature under a nitrogen atmosphere to 10.0 g (0.380M) of 8-bromo-3,1 -dimethoxy-phenanthrene-9-carboxylic acid and the mixture is stirred for 10 minutes. The resulting brown, clear mixture is cooled to -5 ° and 30.4 g (0.1 + 68M) of sodium azide are carefully added in solid form. After stirring for 3 hours at 20 DEG, the reaction mixture is poured onto ice and the resulting suspension is filtered and washed with 1.41 liters of water. The white crude product is suspended in 2.5 liters of ethanol and the reaction mixture is refluxed. After adding 1680 ml of 2N sodium hydroxide, the resulting yellow, clear solution is refluxed for 45 minutes. the solution is cooled to room temperature, extracted with methylene chloride and the organic phase is dried and evaporated. The resulting 9-amino-8-bromo-3β-dimethoxyphenanthrene melts at 107 DEG-1080 DEG. B) 19.4 ml (0.346 M) of formic acid are added dropwise over 5 minutes to a suspension of 614.5 g ( 0.397M) MN-carbonyl-diimidazole in 387 ml of absolute tetrahydrofuran and stirred for 30 minutes at room temperature. This solution is added dropwise over 5 minutes at 0-30 to a solution of 100 g (0.30 μM) of 9-amino-8-bromo-Bβ-dimethoxyphenanthrene in 1600 ml of tetrahydrofuran and the reaction mixture is stirred for 16 hours.

After cooling to -100, the mixture is filtered and the crystals are washed with ether and dried in vacuo. The 8-bromo-9-formylamino] -dimethoxy] ananthrene formed melts at 191 DEG-193 DEG. c) 1000 ml (LUM) of a molar solution of diborane in anhydrous tetrahydrofuran are rapidly added under a nitrogen atmosphere to a suspension of 90 g (0.2l + 9M) of 8-bromo-9-formylamino-Bβ-dimethoxyphenanthrene in 900 ml of anhydrous tetrahydrouran. The resulting solution is refluxed for 1/2 hour and then stirred for 16 hours at room temperature. After the solution has cooled to -5 °, 1800 ml of 2N sodium hydroxide are added dropwise over 5 minutes. The reaction mixture is heated to reflux and the tetrahydrofuran is evaporated at normal pressure. 900 ml of ethanol are added to the hot aqueous solution and the ethanol is evaporated off at normal pressure. 900 ml of ethanol are added and a rotary evaporator is evaporated. The addition of 900 ml of ethanol and evaporation are repeated two more times. The solid, yellow residue is added to 900 ml of methylene chloride and 900 ml of water and shaken with 900 ml of ice. The organic phase is separated and the aqueous phase is extracted three times with methylene chloride (900 ml each time). The combined organic phases are dried and evaporated. The oil formed is emulsified in about 500 ml of hot methanol and methylene chloride is added to form a solution of about 1 liter.

The methylene chloride is removed by heating in a rotary evaporator, taking care not to have two phases. formed. The solution is cooled to -10 ° to give 8-bromo-9-methyl-amino-3,1-dimethoxyphenanthrene, melting at 75-770. D) 70 g (2,202M) of 8-bromo-9-methylamino-Ll -dimethoxy-phenanthrene is dissolved under a nitrogen atmosphere in 700 ml of anhydrous methylene chloride and 139 ml (0.808M) of N-ethyl-diisopropylamine and 38 ml of (OßOLLM) ethyl chloride formate are added. The reaction mixture is stirred for 16 hours at room temperature and extracted with 500 ml of 2N hydrochloric acid. The organic phase is separated and shaken with 500 ml of saturated potassium bicarbonate solution. The aqueous phase is extracted three times with methylene chloride (250 ml each time). The combined organic phases are dried, evaporated and the residue ethyl chloroformate is eliminated by heating at 700 DEG in vacuo.

Crystallization from ether / petroleum ether gives 8-bromo-9- (N-ethoxycarbonyl-N-methyl) -amino-3H-dimethoxy-phenanthrene. (M.p. 100 - 1100). 101.8 ml (0.67M) 1.64 molar solution of n-butyllithium in hexane is added over 10 minutes to a solution of 70 g (0.67M) of 8-bromo-9- (N-ethoxycarbonyl-N- methyl) amino-3β-dimethoxy-phenanthrene in 1890 ml of tetrahydrofuran and 630 ml of n-xa 35e 7905282-5 hexane, stirred at -105 ° under a nitrogen atmosphere. The reaction mixture is stirred at the same temperature for 25 minutes and then allowed to warm to +10 °. After careful addition of 200 ml of water, the reaction mixture is further diluted with 1500 ml of 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-9,10-dimethoxy-5-methyl-1-oxo-dibenz [cd] jindole (m.p. 151-1520 after crystallization from ether / petroleum ether). ).

Example 2 Starting from the appropriate compounds of formula IIIa, the following compounds of formula II can be obtained in a manner analogous to Example 1: (5aRS) -5-ethyl-4,5,5a, 6-tetrahydro-9,10-dimethoxy -dibenz [cdJ] indole (oil) NMR 60 MHz (CDCl 3): δ 4.40 ppm (1H, dd, 10Hz and homoallyl coupling of 1Hz, c-aocH), 1.3 (3H, t, 7Hz, NcH 2 C fl3) ( 5aRS) -4,5,5a, 6-tetrahydro-9,10-dimethoxy-n-propyl-dibenz [cd, f] indole (oil) NMR 60 MHz (CDCl 3): δ 4.40 ppm (1H, dd, 10Hz and homoallyl coupling of 1Hz, C- in a), 1.0 (3H, f, 7Hz, NcH2cH2c_r13).

The starting materials can be obtained as follows: a) 110 ml (0.638M) of N-ethyldiisopropylamine are added to a solution of 100 g (0.302M) of 9-amino-S-bromo-11-dimethoxy-phenanthrene in 500 ml of methylene chloride. A solution of 141.6 ml (0.585M) of acetyl chloride in 500 ml of methylene chloride is added dropwise within 20 minutes to this mixture. During the addition, the temperature of the reaction mixture is maintained at 20 ° by cooling on an 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 2N sodium hydroxide solution and with water, dried and evaporated to give 9-acetyl-amino-5-bromo-Lli-dimethoxyphenanthrene (m.p. 200-202 ° after crystallization from ether).

In an analogous manner, 8-bromo-β-dimethoxy-9-propionylamino-phenanthrene is obtained (m.p. 192 - 1930). b) In a manner analogous to Examples 1c) - le) the following compounds can be obtained: 5-eryl-1ns-dylnym-9,10-dimethoxy-α-oxo-dibenz [cd fl indol (mp 125-125 ° with decomposition) , + +, 5-dihydro-9,10-dimethoxy-β-oxo-5-g-propyl-dibenz [cd] lindol (m.p. 103-1050 with decomposition). 790528245 Example 3 16 β-cyclic acid β-b4dte-α, β-α; dαf = 1 @ _t ° _> (compound of formula II) a) S-bromo-9-ethylamino-3,1β-dimethoxy -phenanthrene 9-acetylamino-5-bromo-β-dimethoxy-phenanthrene is reduced using b) <2) diborane in a manner analogous to Example 1c) to give 8-bromo-9-ethylamino-β-dimethoxy-phenanthrene. (M.p. 103 DEG-1050 DEG after crystallization from ether). 9- (N-Acetyl-N-ethylamino-α-bromo-β-dimethoxy-phenanthrene S-bromo-9-ethylamino-β-dimethoxy-phenanthrene is reacted with acetyl chloride in a manner analogous to Example 2a) to give 9- ( N-acetyl-N-ethyl) -amino-8-bromo-Bβ-dimethoxy-phenanthrene. (Mp 898 ° after crystallization from ethyl acetate).

(LLRQ-S-ethyl-β, 5-dihydro-4-hydroxy-9,10-dimethoxy-β-methyl-dibenz [cd, f] indole i) ii) 10 ml (20 mM) of a 2-molar solution of t_er_t_. butyl lithium in pentane is added at -105 ° to a solution of 14.04 g (11 μmM) 9- (N-acetyl-N-ethyl) amine-S-bromo-BJ1-dimethoxy-phenanthrene in 130 ml of anhydrous tetrahydrofuran and 50 ml of g-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 crude (4RS) -5-ethyl-4,5-dihydro-11-hydroxy-9,10-dimethoxy-1-methyl-dibenzofcd-indlindole formed in the form of a tan foam is further reacted immediately. 2.1 ml (3.3 ml / l) of a 596 g of ethereal methyl lithium solution are added dropwise at -600 to a solution of 1 g (3.3 mM) of 4,5-dihydro-9,10-dimethoxy-5-ethyl-1β-oxo -dibenz [cd fi] indole (prepared according to Example 2b)) in 30 ml of anhydrous tetrahydrofuran. The reaction mixture is allowed to reach room temperature and is kept at this temperature for 30 minutes. The mixture is made alkaline with ZN sodium hydroxide solution and extracted with methylene chloride. The organic phase is dried and evaporated to give (4RS) -5-ethyl-4,5-dihydro-11-hydroxy-10-dimethoxy-11-methyl-dibenz [cdi] indole as a dark green oil (IR spectrum (CH 2 Cl 2): 3550 cm -1 (OH)). The raw product is further processed directly. d) 5-Ethyl-9,10-dimethoxy-1H-methyl-dibenz fcd, fl indolinium chloride 2 ml (10,5 mM) saturated ethereal hydrochloric acid solution is added to 3.2 g (10 mM) crude (4RS) -5-ethyl-4 , S-dihydro-11-hydroxy-9,10-dimethoxy-11-methyl-dibenz [cdf] indole dissolved in 30 ml of ether, whereupon a red product precipitates. After stirring for 30 minutes, the product is filtered to give 5-ethyl-9,10-dimethoxy-1-methyl-dibenz fcd, f] indolinium-10 chloride, which is used immediately for the next reaction. e) (4115) -5-ethyl-1,4,5-dihydro-9,10-dimethoxy-1-methyl-dibenz [cd, fl indole 100 mg (0,3,3 mM) 5-ethyl-9,10-dimethoxy-1-methyl- dibenz [cd, f] indolinium chloride is added to a solution of 12.5 mg (0.33 mM) sodium borohydride in 3 ml of anhydrous tetrahydrouran and 3 ml of ethanol. After a strong reaction, the mixture is stirred for 15 minutes. 3 ml of water are added and the mixture is extracted with methylene chloride.

The organic phase is washed with water, dried and evaporated to give (11RS) -5-ethyl-4,5-dihydro-9,10-dimethoxy-β-methyl-dibenz [cdi] indole as a green oil.

NMR 60 MHz (CDCl 3 δ 1.2 ppm (3H, t, 71-1z, NCH 2 Cl 2 H 3), 1.09 (3H, d, 7Hz, cu-c_H 3), 3.5 (2H, q, 7Hz, Ncg 88 (1H, q, 7Hz, cuH), 6.2 (ii-Ls, ceH), 8.98 (1H, d, 81-lz, ClH).

IR '(cnzcizx 1635 cm -1 (7c = <': - N) f) 5-ethyl-11,5,5a, 6-tetrahydro-9,10-dimethoxy-1-methyl-dibenz fcd, fl indole By reducing The (HIS) -5-ethyl-Ig5-dihydro-9,10-dimethoxy-1-methyl-dibenz [cdi] indole analogous to Example 1 forms the title compound as a mixture of two racemates (oil). The individual racemates can be separated by chromatography on silica gel. i) (T) ~ (4R *, sas ") = NMR mo MHz (cocizh 61, u2 (3H, d, ei-iz, c-awc fl ß), 11) (f) - (4R", 5aR *) = "f" NMR 100 MHz (CDCl 3): Example 1 The following (4RS) -4,5-dihydro-9,10-dimethoxy-dibenz [cd, f] indoles of the formula IIIb, where R 1 and R 2 have it in the meaning given in the table, is prepared in a manner analogous to Examples 3a) -3e) from the appropriate starting materials (the free bases of formula IIIb are obtained as an oil with similar characterization NMR data as described in Example 3e)). Example 18 R1 R2 i CH3 CH3 ii 7 CH3 5-C3H7 iii CH3 'iâg-C337 5 iv CH3 fl- Clíl-lg v - czns ens vi' g; C3H7 CH3 V11 1so-C3H7 CH3 V111 2jC4H9 CH3 10 '_ 1x sec C4H9 CH3 x tert.-C4H9 CH3 X1 2-C5H11 CH3 x11 -CH2-CH2-? H3-CH3 CH3 CH3 Icn e x111 2 J 3 CH3 ~ CH3 15 xiv -ï fl- CH2 ~ CH3, CH3> ° 2 “ The compounds of formula IIIb can be directly converted to the corresponding 9,10-dimethoxy compounds of formula II in a manner analogous to the procedure of Example Bb).

E fi mm2ïááaéæïëuëeååääë @ ë @ && á @ m @ wkë ¥ @ i§wQm®ßf (compound of formula II) '10 15 20 30 35 7905282-5 19 Exemßgl ß szaatft-atfahyag-ai fl eomegxi-szf gin b) t (l) compound of the formula II) (-) - (6aR) -5,6, GaJ-tetrahydro-10,1-dimethoxy-6,6-dimethyl-1H-dibenzo [f] - quinolinium iodide 100 ml (1.6M) methyl iodide is added to a solution of 100 g (0.3l + M) (-1- (6aR) - s, s, ea, 7-fephrahydro <- 10,11-dimeroxy-s-meryl-an-dibem [dough quinone in 100 ml of methylene chloride and the mixture is refluxed for 30 minutes. After cooling, ether is added to the reaction mixture and the precipitate is filtered and dried to give (-) - (6aR) -5,6,6a, 7-tetrahydro-10,1 l- dimethoxy-10-dimethyl-1H-dibenzo [f] g] -quinolinium iodide (decomposition at 173 - 1760) (9RS1-9,10-dihydro-3,4-dimethoxy-9-dimethylamino-5-vinyl-phenanthrene 13.9 g (124 mM) of potassium t-butylate are dissolved under a nitrogen atmosphere in 560 ml of tetrahydrofuran and 47 g (112 mM) of (1- (6aR) -5,6,6a, 7-tetrahydro-10,1l-di- methoxy-6,6-dimethyl- 4H-d1benzo [de, g] quinolinium iodide to lsätts. The reaction mixture is stirred at room temperature for 1 hour, poured onto ice and 560 ml of 1096 g of hydrochloric acid are added. The mixture is washed with ether. The aqueous phase is neutralized with sodium bicarbonate, made alkaline at pH 9 with 50 ml of 2096-g sodium sodium 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 eluent to give (9RS) -9,10-dihydro-Bβ-dimethoxy-9-dimethylamino-5-vinylphenanthrene (m.p. 1090). (4RS) -1}, 5-dihydro-9,10-dimethoxy-1β, 5-dimethyl-dibenz (fd6] indole 17.5 g (57 μM) (9RS) -9,10-dihydro-3,1-dimethoxy -9-Dimethylamino-8-vinylphenanthrene is added to a stirred suspension of 10.2 g (57 mM) of N-bromosuccinimide in 55 ml of water. The reaction mixture becomes hot 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 to give (5aRS) -4,5,5a, 6-tetrahydro-9,10-dimethoxy-ZS-dimethyl-β-methylene-dibenzfcd fl indolinium bromide (which sinks at 1350 and melts at 1650). The raw product is further processed directly. 19.7 g (50.7 mM) of the indolinium bromide formed in 100 ml of ethanolamine are stirred at 1000 for 1 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 give (1ßRS) -4,5-dihydro-9,10-d: mephoxy-αs-dimephyl-dibenz [ma] indole as an oil. (1ßRS1-1-fifi-dihydro-α, 10-dimethoxy-1H-dimethyl-dibenz [cd, f] indole can also be prepared as follows: can be dissolved in a solution of 2.7 g ( 0.86 ml; 17 mM) bromine in 15 ml of chloroform is added dropwise at room temperature to a solution of 4.8 g (1.55 mM) (9RS) -9,10-dihydro-3,4-dimethoxy-9-dimethyleamino -S-vinyl-phenanthrene in 45 ml of chloroform.

After the reaction, the mixture is cooled in an ice bath. The precipitate formed is filtered and washed with 10 ml of chloroform and 100 ml of ether to give 4-bromomethyl-4,5,5a, 6-tetrahydro-9,10-dimethoxy-5,5-dimethyl-dibenz [cd, f] indolinium bromide (as sinter at 1329 and melts at 15.4 - lss °). The product is converted directly: III (ms) -4,4,5-dihydro-9,10-dimethoxy-4,5-dimethyl-dibenz [cd, f] indole by heating in ethanolamine as described above. 4,5,5a, 6-Tetrahydro-9,10-dimethoxy-4,5-dimethyl-dibenz [cdi-1 indole 400 ml (44.2 mM) 396 g of aqueous solution of mercury (II) chloride are added to 200 g (330 mM) zinc dust. The mixture is stirred for 5 minutes and 2500 ml of 2N hydrochloric acid are added. A solution of 15.7 g (50 mM) of (4RS) -4,5-dihydro-9,10-dimethoxylins-dimolyl-dibenz [od, f] indole in 1 ml of ethanol is added and the mixture is heated to 50 ° C. - 600 i ltimme. After adding 200 ml of 37% hydrochloric acid, the mixture is stirred at 90 ° for 14 hours. The mixture is cooled, the zinc dust is filtered and the filtrate is made alkaline at pH 10 with ammonia solution. The mixture is extracted three times with methylene chloride (1000 ml each time) and the combined methylene chloride extracts are dried over Na 2 SO 4 and evaporated to give 4,5,5a, 6-tetrahydro-9,10-dimethoxy-11,5-dimethyl-dibenzfcd fi] indole as a mixture of two racemates in the form of the free base. The mixture of the two racemates is chromatographed on 1.8 kg of silica gel using 50 ml methylene chloride / methanol (98.5: 1.5) fractions as eluent.

Fractions 125-240 contain (II-ÜR *, 5aS *) - 4,5,5a, 6-tetrahydro-9,10-dimethoxy-4,5-dimethyl-dibenz [cdi] indole. NMR spectrum of the base (CDCIB 90 MHz): δ 1.44 ppm (3H, d, 61-1z, C-4oß-Qfi3l, Melting point of the corresponding hydrochloride: from 1850 (with decomposition).

Fractions 250-330 contain (fl-WR *, 5aR *) - 4,5,5a, 6-tetrahydro-9,10-dimethoxy-11β-dimethyl-dibenz [cd, f] indole. NMR spectrum of the base (CDCl 3, 90 M -1 -1): δ 1.24 ppm (3_H, d, 71-1z, C-4/4 -C_H_3). M.p. for the corresponding hydrochloride: from 2000 (with decomposition).

Example 6 In a manner analogous to 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) ([1- (11R) -laaSu- and (3) -4R *, 5aR "1-5-ethyl-4,5, Sαs-tetrahydro-11-methyl-9,10-d] phenoroxy-dibones [od, f] indole ; 10 15 20 25 30 35 '7905282-5 21 (11) (f) - (1 + R *, sas *) - och (3- (4R *, 5ai1 *) - a, 5, scce-fcfrahycxrc-a -mcphyl-sE-propyl-9,10-dimethoxy-dibenz [cd, f] indo1; (Ü- (HÜ, 5aS "') - and (iQ-ULR", 5a R ") -1 +, 5.5a ,--tetrahydro-β-methyl-β-propyl-9,10-dimethoxy-dibenz fcd, f] indole; (iii) (iv) (f) - (4R *, 5aS *) - and ( ILRR * β-silo *) - 5-g-butyl-1,1,5-Saß-tetrahydro-1β-methyl-9,10-dimethoxy-dibenz [cd, f] indole.

Example 7 A solution of 5 g (18 mM) (f) - (11R ", 5aS ° ') -1,5,5a, 6-tetrahydro-9,10-dimethoxy-4,5-dimethyl-dibenz [cd , f] indol in the form of the base in 10 ml of ethyl acetate and 0.5 ml of methanol are added to a solution of 3.3 g (22 mM) (-) - tartaric acid in 22 ml of ethanol / ethyl acetate (1: 1) and the mixture is stirred for one hour at room temperature whereupon (-) - the tartrate of (-) - (4S, 5aR) -4,5,5a, 6-tetrahydro-9,10-dimethoxy-1g dim-dimethyl-dibenz-fcd fl indole crystallizes Decomposition: 183 - 1900; q oqâo: -120.6 ° (H 2 O, c = 0.5) Corresponding hydrochloride, obtained in a known manner, decomposed at 210 - 2550; = 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 (ca. 2.5 g; 9 mM) is mixed with 1.65 g (11 mM) in 11 ml of ethanol / ethyl acetate (1: 1). After stirring for one hour at room temperature, the tartrate crystallizes from (+) - (4R, 5aS) -4,5,5a, 6-tetrahydro-9,10-dimethoxy-Ig fi-dimethyl-azbcn flccgfindcl. sundcfdclning: 1: 5 - 19o °; ME ° = + 11e ° (H 2 O, c = 0.5). ncn pa kan: san crhauna hydrckicfiacn söndcracladcs vid 215 - 2zo °; [α] D = + 1uo ° u12o, c = 0.5). (+) - tartaric acid The following compounds can be obtained in an analogous manner from (t) ~ (4R *, 5aR *) - 4,5,5a, 6-tetrahydro-9,10-dimethoxy-QJ-dimethyl-dibenz [cd fi] indole (in the form of the free base): - (-) - the tartrate of (+) - (# S, 5aS) -1 +, 5,5a, 6-tetrahydro-9,10-dimethoxy-IgG-dimethyl-di- bcnsfcrgflindcx. söndcrdcining: 177 - 1so °; EMEÉÛ = + 11th ° (H 2 O, c = 0.5). sanacfacining of the corresponding hydrochloride; leo _ 164% lßlšf) = + 1eo ° (H 2 O, c = 0.5). - (+) - the tartrate of (-) - (4R, 5aR) -4,5,5a, 6-tetrahydro-9,10-dimethoxy-1β, 5-dimethyl-dibenzene dc-indole. Decomposition: 178 - 1820; ÜQÉO = -1 WO (HåJO, C = 0.5) - Decomposition of the corresponding hydrochloride: 158 - 1620; ÜÜD = -1560 (H 2 O, c = 0.5). I 79052182 - S 10 15 20 22 I The following compounds can also be obtained in an analogous manner from (n- (fi R flfi aSÜ- fi-ethyl-4,5,5a, 6-tetrahydro-9,10-dimethoxy-1-methyl-dibenz [ cdpf] indole (in the form of the free base): (J-tartrate of (+) - (4R, 5aS) -5-ethyl-4,5,5a, 6-tetrahydro-9,10-dimethoxy-le-methyl - dibenz [cd, f] indole; LBÜÉO = + 96 ° (H 2 O, c = 0.5) Corresponding hydrochloride obtained in a known manner was decomposed at, 185 - 1880; (0.5). (+) - the tartrate of (-) - (# S, 5aR) -5-ethyl-4,5,5a, 6-tetrahydro-9,10-dimethoxy-1β-methyl-dibenzfcd-indole; : -102.1 + ° (H 2 O, c = 0.5) Corresponding hydrochloride, obtained in a known manner, decomposed at 189-190 °; CWJ â0 = -l22 ° (H 2 O, c = 0.5) ßxemæl s Qaea fi zas fl fazas Tylphenyl (Compound of Formula I) g 16.8 g (53.8 mM) Gil-MR *, 5aS ") - β, 5,5a, 6-tetrahydro-9,10-dimethoxy- 11β-Dimethyl-dibenzofcindhindole is dissolved in 400 ml of 11 DEG-796 DEG C. aqueous solution of hydrobromic acid and the solution is heated for 3 hours at 1300 DEG C. After evaporation of the mixture. The residue is dissolved in ethanol and the solvent is evaporated. Crystallization of the residue from methanol / ether gives the hydrobromide of the title compound. The corresponding hydrochloride obtained in a known manner was decomposed at 185 °; NMR 100 MHz (DMSO): δ 1.81 (3H, d, 5Hz, c-uu-CEB).

Example 9 ~ 39 - _ _ In a manner analogous to Example 8 and using the corresponding starting material, one can obtain. compounds of formula Ia, in which R 1 and R 2 have the meaning given in the table.

LO 7905282-5 23 Decomposition Ex- R R2 Configuration [(1120 (HO 'D 2 c = O .5) 9 CH3 CH3 (f) - <4R * .5aR *> 18S ° 1)' l) 10 cH¿ CH3 (-) - (4S, 5aR) 1ss ° [u] š ° - -97 ° 11 cH3 cH3 (4) - (4R, 5aS) 1ss ° 17 [«1š ° = + 96 ° 12 CH3 CH3 <+> - <4s.sas> 215 ° 1> [q1š ° = + 136 ° 13 CH3 CH3 <-) - (4R.san) 20S ° 1) 1u1š ° _ 13s ° 14 cn3 czus (-) - (4S.5aR) ï > 2so ° 2) la] 2 ° = -es, 7 ° 15 C53 CZH5 (f) - <4R *, 5aR *> 19s ° 1> 16 cn3 c2H5 (f) - (4R *, 5aS *) 19o ° 1 ) 1 17 CH3 ¿~ C3H7 (f) - (4R * .5aR *) l80 °) 18 CHB ¿; c3n7 (f) - <4R * .ßaS *> 1so ° 1) 1 19 CH3; §9-c3H7 ( fl- (4R * .5aR *) 205 °) ~ + -k * ° l) 20 CH 1so-C3H7 (-) - (4R, 5a5) 220 21 cn ¿; c4H9 (f) - (4R *, saR * ) 16o ° l) 22 cu ¿; c4H9 (3) - (4R *, sas *) 21o ° 1) 23 H ena (ï) - (saRs) 210-z7s ° 2) lO l5 7-905282-5 zu EX . R I 32 Con guration Song division 1. m0 (H20. c = 0-5) _ "- + I QZ) 24 H czus (-) - (5arzs)> 24o _ ~ + l) 2 :: H r_1_-C3H7 (-) - (SaRS) 258- 260 26 czus cH3 '(ï) - (4R *, 5arz *)> 175 ° 2) zv czas ca3 (lï- (aansaf fl f) 71993 * 2 28 i _. = ¿<_> -c3 fl7 cn3 (ïÜ- (awqsaan> 22s °) - + 02) 29 __s __- C3H7 CH3 (_) - (4R *, 5aS *)> 20O _30 _1_1_-c3u7 C113 (ï) - (4R *, san *) _> 21s ° 2) 31 g- c3n7 cn3 (f) - (4R *, sas *)> 1as ° 2) 32 çertfcqng cn3 (ï) - (4R *, sa11 *) 2814-2853) 33 tšft = c4f19 C113 (ïï-Mansasn zvo-zvrz) 34 secfcêng m3 (lU-uRnsaRn 263-269 ”35 secfcqng cn3 (ï) - (4R *, sa“ s *) 28S-286 ° 2) 36 gäng C113 (ïy-mnnsaa fl 2723) 37 _n_ ~ c4f19 c fl3 (f) - (4R *, sas *) zes-zvrz) en. Se -cu / | 2 C113 - <4R *, ßa11 *> nom \ cH2 - / cnz + 2) 39 _CH \\ (_33 (-) - (4R * , 5as. *) 25s-2s1 ° cnz 1) hydrochloride 2) hydmbmmid \ 10 15 7905282-s 25 Exemæl 40. (fl-lfßßiáaSfkâiLëhdàsnë fl wßet fl l fi l fi eáiëæhyffahleådifnelvlfl- gibel (gibel) to a solution of 1.3 g (1531 mM) (f) - - (1 + R * gas *) - a, s, sa, e-tefrahydro-9,1o-dihydroxy-u, s-dimeryl-dibenz [ caps] anda-hy hydrochloride in 12 ml of trifluoroacetic acid and the mixture is refluxed for one hour. After evaporation of the reaction mixture, the residue is extracted three times with methylene chloride (100 ml each time) and the combined organic extracts are dried over sodium sulphate and evaporated. The residue is purified by chromatography on a column of 165 g of silica gel using methylene chloride / methanol (97: 3) as eluent to give pure (fl-ULR *, 5aS *) - 9,10-dibenzoyloxyl-ÅL, 5.5a, 6 -tetra- hydro-lfß-dimethyl-dibenz fl cd fl indole. The hydrochloride melts at 215-225 ° (with decomposition) after crystallization from ether / acetone; NMR 100 MHz (DMSO): δ 1.39 ppm (3H, d, 6Hz, C-1m-C 1a).

Examples 41-105 In a manner analogous to Example 40 and using the corresponding starting material, one can obtain compounds of the formula R and R "where R 1, 2 have the meanings given in the following table. 7-905282-5 TABLE 11 ÄEx. RR - Decomposition _ 1 2 mš fl (c = os> 41 H -cn3 .QCI 189 191 ° lm ¶ _ m) 42 H czns 1ss ° 43 H 'Fi-WH -cuz-G 21o-z13 ° l) 7) 44' n -g-c3n7 21o-213 ° U7) / \ _ __ CF _ 2) 7) 45 C113 cz fl s' Q 214 219 ° __ _ 2) 7) 467 CH3 CZHS 2lO-2l3 ° _ __ 2) 7) 47 ena. czns z32-239 ° _ _ 2) 7) 48 C113 02115 19e-2oo ° 49 -cH3 -czns .Q-cl 235-238 ° 4) 7) 4 [«1š ° (11 @ o11) -32.-s ° 50 -CH3 -CZHS -Qcl 221-223 ° 5) 7) [41š ° (> 1 @ o11) + zs.4 ° 51 -CH3 -3- (13117 l58_l69 @ 3) 7) 52 -cns -yC3H7 2Qs -212 ° 3) 7) 7905282-5 27 EL RRR "Decomposition 1 2 3 [GJšO (c = o.5) 53" GHz "2" ° 3 "7" (CH2) 3'CH3¶ lss-lel fl m 54 " wa "'PÉC3H7' Cz 2 s 2o5-zo1 ° 3) 7) OCH3 se -CH -CH / \ CH 1s1-1e3 ° 5) 7) 3 2 5 3. zo - [GJD (Meon) + 18.8 ° cH 3. 57 -cn3 -czns -G-cl 1793) "58 -CH3 -Cz fi s / \ 133_l9O ° 2) 7) cl> 18s ° 6) 7) - -c H 59 CHB 2 5 'Q [a] š ° (Meorx ) -21,2 ° cl _ j zm 60 cn3 _0255 _®-ocn3. ¶169-173 «> 61 244-245 ° 5) 7) -c -c H H3 _ 2 5 OCHB [a] š0 (Meou) + 26 ° 7905282 ~ 5 ¶ ax. RRR Sönderdehüng l «1š ° (c = 0.5) 62 -CH3 -CZHS _« <::> í ocn 63 "CH3 7 -CZHS - _íš ::> ~ o 54 _CH3 -cn3 -cH2 + á ::> LH CH. , / 2 CHZ '57 _CH3 -CH3 - -c fl2) 2- CH3 68 ~ CH3 -CH3 7 --CH3 69 ~ CH3 ~ E-C3H7¶ -iso-C3H7 10 -CH3 -3-c3H7 - {<:: > 71 -cH3 -3-c3H7 -text.-c4H9 72 ~ CH3 -E-C3H7 -iso-C3H7 '73 _ -CH3 -çz fl à - «<::>; CH3 74' CH3" cz fl sí - «<::> »Cu 3. 203-2O5 ° 2) 7) 2l8 ~ 223 ° 2) 7) 221 ° 2) 7) 213 ° 2) 7) 193-199 ° 2) 7) zo4 ° 2) 7) 2io ° 3) 7) 201-2o7 ° 2) 7) l93 ~ l97 ° 2) 7) 2o8 ° 2) 7) zos-zo7 ° 2) 7) z1o ° 5) 7) [«] š ° (neon> + 1s.ß ° 10 7905282-5 29 E _ RRR "Sönderdelning x 1 2 3 [qš fl 75 -ci13 -cz fl s Q 2O5_208 ° 2) 7) cu3 76 -cn3 -czns _ñ§ ::> l94_l96 ° 2) 7) ac _ 77 - cn3 -cu3 _ñ <:::> l58_l74 ° 3) 7) 78 'CH3 * H3 -tertwcllag 2063) ”79 -CH3 _cH3 _iso_C3H7 l94_2o2 ° 2) 7) so -cn3 -CH3 / \ 215-23s ° 5) 7 ) __ zo _ 0 [«] D (H20) se. 5) 7) 81 -cu3 -cn3 -lsø-c3H7 2š5-225 ° [@] D ° (H2o) -1e6 ° 2) 7) _ _ ler-1so ° 82 -C713 0,15 @ »3) 7) _ _ leo-19s ° 214-221 ° 5) 7) 2 [«1DO (M @ ou) + 1z ° 10 7995282-s 30 Ex. RL Rz Ra Decomposition [fl lšo (c = 0 ~ 5) __- _ _ _.> 2) 7) 85 -cH3 c2H5 tert. c4H9 170 185 _ 86 -CH -CH -tert.-CH 18O ° 6) 7) 3 2 s 4 9 20 '2 mn (nafn-ulf _ _ _ "_' 'an 87 cH3 czns tert. c4H9 225.235») 88 -CH3 -cz fls -iso-c3H7 l35__l5O »2) 7) 89 -CH3 -czna -isb-c3H7 220_23O = 3) 7) 90 -CH3 -CZHS -cnz- {í ::} - QCH3 136-142 ° 2 ) 7) - _ 163-171 ° 6) 7) -CH _ '_ ~ 91 3 Cz fl s C "2" ® “° C" 3 [«1š ° (1 ~ x @ on) -es.1 ° 92 - CH3 -CZHS -lcx-1 135_l42 ° 2) 7) ocH3 93 ~ cn3 -czßs ~ cH2 {§ ::> l33_l4O ° 2) 7) cH3o. 94 'm3' Cans -cu2_®_c1 2oo-21z ° 2) 7¿) 6) 7) 95 -CH -e H 123-133 ° 3 ._. 2 5 CHTQ * Cl [u] š ° çr-1eofn-ee.z ° 31 1905282-s Ex 'R1 Rz RÅ' 96 _ _ -cn - 1 1 _ _ -ca 971 CH3 Cz fl s 2: § ::> c <_ _ -cn - 18 cu3 czns 2 ~ ¶ :::> _ ç1 c1 99 ~ cH3} -c2H5 _CU2_§š'ï c1 1oo -CH3 -CZH5 _CH2_í§ ::> F_Cl cl 1 íí - 101 -CH3 ~ c2H5 -CH2 __ 1 102 -CH3 _-cz fl s / \: ======== :: ==== :: = [«] š ° (M @ on) -7e.3 ° 187-l9l ° 210-2l2 ° 199-2l4 ° Sönderdehüng [«] å0 (c = o.5) 199-zo3 ° 2) 7) 154-16l ° 2) 7) 136-142 ° 6) 7) 239-244 ° 2) 8) 2) 8) 2) 8) 2) 7) 10 7905282-5 32 Ex. R R R "I Decomposition 1 2 3 [fqš fl 103 -Cfß" C2H5 V lea-leva "I F 105 -cH3 -cu3 I-CHZQ 20ß ~ 2l0 ° 6) 7). '[«1š °. 1) (f) 2) (f) (4R *, sas *) 3) (f) (4R *, saR *) 4) (-) mmsas) s) (+) ç4s, sa1z) 6) <-> ¶ <4s, 5aR> 7) hydrochloride 3) methanesulionate The end products of the invention, especially the compounds of formula I, have pharmacological activity. In particular, the compounds are indicated for use as central dopaminergic stimulants, as indicated by standard tests, for example according to the principles of U. Ungerstedt Acta Physiol. Scand. Suppl. (1971) 3_6_7, 69-93, by induction of contralateral twisting in rats whose substantia nigra has been damaged by microinjection of S-hydroxidopamine, and by induction of dose-dependent stereotyped sniffing, licking and biting behavior in rats according to the following test : Rats, 180-222 g, are placed in plexiglass cylinders with a diameter of 30 cm on a wire mesh floor. After 30 minutes to allow acclimatization to the cage, the rats are injected with the test compound. The behavior of the rats is observed for 2 minutes at 30 minute intervals for two hours and then at 60 minute intervals up to a total of seven hours. The observed degree of stereotyped behavior is evaluated using a computational system based on that described by Costall, Naylor and Olley (Euro J. Pharmac. 1-8, 83-94 (1972)). the valuation and criteria are as follows: l. Intermittent sniffing 2. Permanent sniffing, temporary licking, 3. Licking, temporary biting, ll. intense and permanent biting.

In these tests, the compounds are administered i.p. from 0.03 to 30 mg / kg d body weight.

The compounds are therefore indicated for use as central dopaminergic stimulants, for example for the treatment of Parkinson's disease. For this indication, a daily dose of from about 0.5 to about 100 mg may be indicated, suitably administered in sub-doses of 2 to 11 times daily in unit dosage form containing from about 0.1 to about 50 mg, or in a sustained release form.

The compounds of Examples 50, 51+ to 61, 611, 73, 71+, 81, 82, S11, 85, 86, 90, 91, 94, 95, 97, 98 and 105 are of particular interest, especially the compounds of Examples 50, 57 and 61+. The compounds may be administered in the form of pharmaceutically acceptable acid addition salts. These salt forms exert an activity of the same order of magnitude as the free base forms. The present invention also relates to pharmaceutical compositions containing a final product according to the invention, in particular a compound of formula I, in the form of the free base or pharmaceutically acceptable acid addition salt, in

Claims (9)

3.4 combination with a pharmaceutically acceptable diluent or carrier. These compositions may be formulated in conventional manner to be, for example, a solution, a capsule or a tablet. CLAIMS i. U, s, sa, s-: errahydro-dibenz [cd, f) indo1, characterized in that it has at least one oxy substituent in one or both of the fused benzene rings, at least one such oxy substituent is hydroxy or acyloxy when the nucleus is unsubstituted in the 1ß position, in racemic form or in optically active form. A compound according to claim 1, characterized in that it has the formula wherein R 1 is hydrogen or (C 1-10) alkyl, (C 3-7) cycloalkyl or (C 3-7) cycloalkyl- (C 1-8) alkyl, R 2 is (C 1-5) alkyl, and the R 8 substituents are the same and consist of hydroxy or acyloxy groups, I in raceric form or in optically active form. A compound according to claim 2, characterized in that it has the formula Ia - I \ HO / / R1 I I Ia \ N-nz wherein R 1 and R 2 have the meaning given in claim 2. 10 15 20 25 30 _characterized 7905282-5 35 A compound according to claim 1, characterized in that it has at least one ether group in one or both of the fused benzene rings and is substituted in the IL position in the core, in racemic form or in optically active form. A compound according to claim 1, in that it has at least one ether group on any of the fused benzene rings, with the proviso that when there is more than one ether group these are attached to the same fused benzene ring. A compound according to any one of claims 1, 1 and 5, characterized in that the ether group is a methoxy group. A compound according to any one of claims 1-6 in the form of an acid addition salt. A process for preparing a 4,5,5a, 6-tetrahydro-dibenz [cd, f] indole having at least one oxy substituent in one or both of the fused benzene rings, at least one such oxy substituent being hydroxy or acyloxy when the nucleus is unsubstituted in the II position, characterized in that i) a compound containing at least one ether group is prepared in one or both of the fused benzene rings by reducing the 5a, 6-double bond in a corresponding ÅLJ dihydro-dibenz [cd, f) indole, which is correspondingly substituted or oxo-substituted in the 4-position when it is desired to prepare a compound unsubstituted in the li-position, or ii) prepares a compound containing at least one hydroxy substituent in one or both of the condensed benzene rings by cleaving the ether group (s) in a corresponding compound containing at least one leaving group ether in one or both of the fused benzene rings, or. iii) preparing 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 substituent in one or both of the fused benzene rings. Pharmaceutical composition, characterized in that it contains a compound according to any one of claims 1 to 6 in the form of a free base or a pharmaceutically acceptable acid addition salt in combination with a pharmaceutical carrier or diluent. 7905282-5 '10 SANSMANDRAG 4,5,5a, δ-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 li position. In particular, compounds of formula I "g (I) wherein R 1 is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, R 2 is alkyl and the R B substituents are the same and are hydroxy or acyloxy groups. The compounds have pharmacological activity and are specifically indicated for use as central dopaminergic stimulants. Furthermore, intermediates and processes for the preparation of the compounds as well as pharmaceutical compositions containing them are described.