FI70407C - FREQUENCY REFRIGERATION FOR THERAPEUTIC THERAPEUTIC ANALYZLE 4,5,5A, 6-TETRA-HYDRO-DIBENS / CD F / INDOL DERIVAT - Google Patents

Description

I • -ft # ** 3 '"·! Tri advertisement.su οη4Ω7 · $ 8Γίί B 11 UTLÄGG NIN G SSKRI FT / UhU / C (ak \ Pitccitti iny ^ :; wcoty 1 ^ ¾] (4S) Fater.t Kc.'Xelst 13 33 1330 (51) Kv.llc. * / Lnt.CI.4 c 07 D 209/90 FINLAND FINLAND (21) Patent application - Patentansökning 791912 (22) Application date - Ansökningsdag] I4 # 06,79 (23 ) Starting date - Giltighctsdag 1 4, 06.79 (41) Made public - Blivit offentlig 2 ^] 2 79

National Board of Patents and Registration Date of publication and publication

Patent and registration authorities '' Ansökan utlagd och utl.skriften publicerad 27 * 03 .86 (86) Kv. application - Int. ansökan (32) (33) (31) Privilege claimed — Begärd priority 23 * 06.78 23.O6.78 Switzerland-Switzerland (CH) 6873/78, 6874/78 (71) Sandoz AG, 35 Lichtstrasse, 4002 Basel, Switzerland Schweiz (CH) (72) Rudolf KA Giger, Riehen, Switzerland-Schweiz (CH) (7 * 0 Oy Koi ster Ab (54) Method for the preparation of new therapeutically useful 4,5,5a, 6-telrahydro-dibents / cd, fjindole derivatives - Förfarande för f ramstä11 Ning av nya, therapeutiskt användbara 4,5,5a, 6-tetra-hydro-d ibens / cd, f./i ndol der ivat

The invention relates to a process for the preparation of new therapeutically useful 4,5,5a, 6-tetrahydro-dibenz / cd, E7 indole derivatives of the formula I

wherein R 1 is hydrogen, () alkyl or () cycloalkyl, R is (C 1 -C 6) alkyl L and the R 4 substituents are the same and represent hydroxy or acyloxy of formula 2 70407 R -CO-O- a wherein R 1 is optionally substituted alkyl; (C 3 _?) Cycloalkyl-yl; or optionally substituted phenyl; and pharmaceutically acceptable acid addition salts thereof.

R 1 is preferably alkyl suitably containing 1 to 6 carbon atoms and may represent, for example, methyl.

R 1 is suitably alkyl having 1 to 4, preferably 1 to 3, carbon atoms.

R 1 substituents are preferably acyloxy groups of formula R 0 -O-a wherein R is optionally substituted alkyl; (C) cycloalkyl; or optionally substituted phenyl.

When R is alkyl, it may suitably contain 1 to 17 carbon atoms, preferably 1 to 7 carbon atoms, and be straight-chain or branched.

R may be substituted alkyl having d suitably 1 to 5 carbon atoms in the alkyl chain. Suitably it is monosubstituted alkyl. Examples of substituents are carboxy, hydroxy, amino, (C 1-4) alkylamino, (C 1-4) alkoxy, di- (C 1-4) alkylamino, halogen, (C 1-4) alkylthio -, phenoxy, phenyl, 1-pyrrolidinyl, piperidino and morpholino groups, however, the most suitable substituent is phenyl. R may also be, for example, alkyl having 1 to 4 carbon atoms in the alkyl chain and substituted by a (C 1-4) cycloalkyl group. When R is phenyl or phenyl-substituted alkyl, cl may be unsubstituted or contain 1, 2 or 3 identical or different substituents which may be, for example, halogen, trifluoromethyl, () alkyl, (C 1-4) alkoxy, (C 1-4) alkoxy, ) alkyl lithio, di- (C 1-4) alkylamino or methylenedioxy. Preferably phenyl is mono- or di-substituted.

When R is a phenyl-substituted alkyl group, R is preferably benzyl. The phenyl ring may have substituents which may be, for example, halogen, () alkyl, (C 1-4) alkoxy or (C 1-4) alkylthio.

3 70407

Preferably is (C 1-6) alkyl; () cycloalkyl; unsubstituted phenyl; phenyl mono- or disubstituted with chloro, fluoro, trifluoromethyl, (C 1-6) alkyl or () alkoxy; unsubstituted benzyl; or benzyl mono- or disubstituted by chlorine, fluorine, (C 1-4 alkyl or () alkoxy.

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

The process according to the invention for the preparation of the compounds of the formula I is characterized in that a) a compound of the formula Ia OH is prepared.

"1 (ia}

wherein R 1 and are as defined above, by cleavage of the ether groups Z from a compound of formula II

"JSK '·'

uj-X

wherein R 1 and R 2 are as defined above, and Z is a cleavable ether group, or b) preparing a compound of formula Ib R 3 r; J II J k OCn ^ (Ib) „70407 wherein R 1 and are as defined above and the R 1 substituents are similar and represent acyloxy of formula R 0 -O-a wherein R is as defined above by acylation of formula Ia and the resulting compound is recovered as the free base or a pharmaceutically acceptable acid addition salt.

The ether cleavage according to the invention (method a) can be carried out in a manner known per se for the cleavage of ether groups. For example, the reaction can be carried out by treating the starting materials with a concentrated mineral acid, e.g. hydrobromic 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, especially at 130 ° C. The ether groups Z 1 are preferably arylalkoxy or alkoxy groups containing up to 10 carbon atoms, especially benzyloxy, ethoxy or methoxy groups, most preferably methoxy groups.

The acylation process according to the invention (process b) can be carried out in a manner known per se for the selective acylation of phenolic groups in the presence of an amine function. As the acylating agent, for example, a functional derivative of an acid such as acid chloride, acid bromide or acid anhydride can be used. Suitably the reaction is carried out by reacting the acid chloride 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 room temperature.

In process variant a), the 4,5,5a, 6-tetrahydro-dibenz / cd, f-indoles of the formula II used as starting materials, which contain two ether groups in one of the fused benzene rings, can be prepared by reduction of the 5a, 6-double bond in the corresponding 4,5-dihydro -dibenz / cd, E / indole, respectively substituted, or oxo-substituted at the 4-position when a compound unsubstituted at the 4-position is desired.

5 70407

In particular, compounds of formula II can be prepared by reduction of the 5α, 6-double bond, and removal of the 4-oxo group in the compound of formula III

Z

I i1 I / X

wherein R 2 and Z are as defined above and either X is hydrogen and Y is the same as R, or X and Y together form an oxo group.

The reduction can be conveniently carried out by methods conventionally used for the reduction of enamine or imines, e.g. with zinc in aqueous mineral acid solution, preferably aqueous hydrochloric acid solution, optionally in the presence of mercury II) salt, e.g. mercury (II) chloride. The reduction may conveniently be carried out in an organic solvent, e.g. a lower alkanol, e.g. ethanol, and at a temperature between 50 ° C and the boiling point of the reaction mixture. Under these conditions, any II-oxo group present is simultaneously removed.

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

The compounds of the invention have an asymmetric carbon atom in the 5a-position and can be obtained as a racemate or another optically active form, i.e. as individual enantiomers.

When a compound has a substituent at the 4-position, especially when R 1 in formula I is other than hydrogen, the compounds of the invention have two asymmetric carbon atoms in the 4-position and 5a-positions and therefore two racemates may exist. Starting from optically active starting materials, optically active end products can be obtained. Racemic starting materials give racemic end products. The racemates can be separated into the enantiomers by known methods, e.g. by fractional crystallization of diastereomeric salts, e.g. fractional crystallization of their salts with (+) or (-) tartaric acid or di-p-toluyl-1- or d-tartaric acid. Separation of racemates can be performed at the end of the synthesis or, if desired, at an earlier stage. Preferably, the separation of the isomer is performed before cleavage of the ether groups.

Compounds of formula III in which X is hydrogen and Y is other than hydrogen contain an asymmetric carbon atom in the 4-position. Upon reduction of these compounds, a second asymmetric carbon atom is formed at the 5a position.

Compounds of formula lila

Z

r Vs!

Ji lo z ..... lila ΙΠ _n-r2 where R2 and Z have the same meaning as above can be prepared, for example, according to the following reaction scheme.

'' ^ ^ Hal - ^ Z- Onui C00H NH,

IV V

z V

yVXHal <- Ha!

VII '^' '^ NH-CO-RJ

VI

F | f * | 2 I "___ ^ lila ^^ \ ^ Si-C00-Alk i VIII R2 / 70407

In the reaction scheme, Z and R 2 are as defined above, R 1 is hydrogen or (C 1-4) alkyl, Hal is iodine, bromine or chlorine and Alk is lower alkyl. The reactions can be carried out in the usual manner.

Compounds of formula V may be prepared according to a variant of the Curtius reaction, for example by reacting an acid of formula IV with sodium azide in the presence of trifluoroacetic acid or trifluoroacetic anhydride followed by hydrolysis with a base. For example, acylation of compounds of formula V may be performed with a compound of formula R "2-CO-Hal, wherein Hal is as defined above and R" 2 is (C 1-4) alkyl, in the presence of an acid acceptor, e.g. N-ethyldiisopropylamine . When R "2 is hydrogen, the reaction may be carried out by reacting a compound of formula V with formic acid in the presence of N, N-carbonyldiimidazole. Compounds of formula VI may be reduced, for example, with diborane. Compounds of formula VII may conveniently be prepared by reacting a compound of formula VII with chloroformate in an organic solvent and in the presence of an acid acceptor, e.g. N-ethyldiisopropylamine Treatment of compounds of formula VIII with e.g. an alkyl or aryllithium compound, preferably n-butyllithium or tert-butyllithium in tetrahydrofuran / hexane at -110 ° C 0 ° C yields compounds of formula IIIa.

* + - Oxo-substituted compounds of formula III in which X and Y together form an oxo group can be prepared analogously to compounds of formula IIIb

Z

z R1 IIIb 8 70407 wherein Z, R1 and are as defined above can be prepared, for example, according to the following reaction scheme wherein Z, (r) R, R2 and Hal are as defined above and AnV- / is an anion:

IX

V

Ψ 7 1, ^ tx <^ / ^^ X'N-CO-R1 xi X R2

V

^ iiib © 0

an

The reactions can be carried out according to known methods. The acylation of compounds of formula V can be carried out, for example, by reacting a compound of formula Hal-CO-R *, wherein R 1 represents the same as R 1, provided that R 1 is not hydrogen and Hal means the same as above, to react in the presence of an acid acceptor e.g. N-ethyldiisopropylamine. When R 1 is hydrogen, the reaction can be carried out by reacting a compound of formula V with formic acid in the presence of N, N-carbonyldiimidate-Sol. The compounds of formula IX can be suitably alkylated with alkyl iodide under phase transfer catalysis conditions, e.g. in the presence of tetrabutylammonium hydrogen sulphate. Treatment of compounds of formula X with e.g. n-butyllithium or tert-butyllithium in tetrahydrofuran / hexane at -110 ° C to -D ° C affords compounds of formula XI. The dehydration of the compounds of the formula XI can be carried out, for example, with a mineral acid, for example with hydrochloric acid in ether. Salts of formula XII can be reduced to compounds of formula IIIb with sodium borohydride in tetrahydrofuran.

Compounds of formula X may also be prepared in a conventional manner from compounds of formula VII by acylation with compounds of formula R 1 -CCO-Hal as described above.

Compounds of formula XI in which R1 is as defined above may also be prepared in a conventional manner from compounds of formula IIIa by reaction with compounds of formula R1 in which 'is as defined 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 LiAlH 2.

Compounds of formula IIIb wherein R 1 is methyl may also be prepared according to the following reaction scheme wherein Z and R 0 are as defined above, Halo chloride, bromide or (C 1-4) iodide, An'- is chloride, bromide, iodide, CH 2 -SO 2 or and either R x is hydrogen and R 2 is bromomethyl or R 2 and together denote the group = CH 2: 10 70407

An © 1 / \ XIII CH3 r 'CH3

XIV

j IX

LnII 1 — ®N-CH, y ___ z ~ f ^ 7f ^ SlScH = CH

Ha! © KAJ \

XVI 2 N-CH

i J

?

IIIb (wherein R1 is CII3) XV

Alkylation of compounds of formula XIII may be carried out e.g. by reaction with compounds of formula An-R 1, wherein R e is as defined above and Ar is chlorine, bromine or iodine, or when R e is a methyl or ethyl group, the alkylation may be carried out by reaction with dimethyl - or with diethyl sulphate. The ring opening of the compounds of formula XIV may conveniently be carried out with an alkali metal alcoholate, preferably potassium tert-butylate in dimethoxyethane, dioxane or tetrahydrofuran, at a temperature of 0 ° C to 50 ° C, preferably at room temperature.

The preparation of compounds of formula XVI from compounds of formula XV may be carried out under oxidizing conditions with e.g. bromine or halogen releasing compounds, e.g. N-bromosuccinic acid amide. The region-selective cyclofunctionalization of a compound of formula XV to a compound of formula XVI with bromine may be carried out at 0 ° C to 50 ° C, preferably at room temperature, in a suitably inert organic solvent, e.g. halogenated hydrocarbon, e.g. methylene 70407 nichloride, chloroform or carbon tetrachloride. preferably in chloroform. The reaction with N-bromosuccinimide can be suitably carried out at 0 ° C to 50 ° C, preferably at room temperature in the presence of water and optionally in the presence of an organic solvent, e.g. dioxane, tetrahydrofuran, methylene chloride or chloroform. The demethylation of the resulting quaternary compounds of formula XVI, followed by rearrangement, is suitably carried out at a temperature above 80 ° C, preferably at a temperature of 80 ° C to 110 ° C, especially at 100 ° C, in an organic solvent, e.g. benzene, dimethylformamide or in ethanolamine, preferably in ethanolamine.

The products of the above reactions can be isolated and purified in a known manner.

If the preparation of a particular starting material is not specifically described, this may be prepared in a conventional or analogous manner.

Certain starting materials are novel and are particularly useful intermediates in the preparation of pharmacologically active compounds.

The compounds of formula I have pharmacological activity. In particular, the compounds are proposed for use as key dopaminergic stimulants, as shown by standard experiments, for example, U. Ungerstedt Acta Physiol.

Send. Suppl. (1971) 367,69-93, by inducing a contralateral reversal in rats whose substantia nigra has been injured by microinjection of 6-hydroxydopamine and by inducing a dose-dependent schematic of olfactory, licking and biting behavior in the rat according to the following experiment:

Rats (180-222 g) are placed in 30 cm diameter plexiglass cylinders on a wire mesh floor. After adaptation to the cage (30 min), the rats are injected with the test compound. The behavior of the rats is humified for 2 minutes every 30 minutes for 2 hours and then every 60 minutes for a total of 12,70407 for 7 hours. The degree of schematic behavior considered is evaluated using a system based on the evaluation system described in Costall, Naylor and Olley (Euro, J. Pharmac, 18, 83-94 (1972)).

The criteria for the result are as follows 1. Intermittent sniffing 2. Relentless sniffing, occasional licking 3. Licking, occasional biting 4. Passionate and relentless biting.

In these experiments, the compounds are administered intraperitoneally at 0.03 to 30 mg / kg of animal body weight.

The compounds are therefore proposed for use as key dopaminergic stimulants, for example in the treatment of Parkinson's disease. The daily dose indicated for this indication is from about 0.5 to about 100 mg, suitably administered in divided doses 2-4 times a day in unit dosage form containing from about 0.1 to about 50 mg or in a slowly absorbed form.

The compounds of Examples 50, 56 to 61, 64, 73, 74, 81, 82, 84, 85, 86, 90, 91, 94, 95, 97, 98 and 105 are of particular interest, very particularly of interest are those of Examples 50, 57 and 64 compounds.

The compounds may be administered in a pharmaceutically acceptable acid addition salt form. These salt forms have the same class of activity as the free base forms.

In the following examples, all temperatures are given in degrees Celsius and are uncorrected.

The absolute configurations of the optically active compounds of formula II corresponding to Example 7 and in which Z is a methoxy group and R 1 and R 2 are methyl groups were determined by X-ray analysis. The absolute configuration of the other optically active compounds of formula II was determined analogously by 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.

i3 70407

Example 1 (5aRS) -4,5,5a, 6-Tetrahydro-9,10-dimethoxy-5-methyl-dibenz / cd, 7-indole (Compound of Formula II) 544 ml (0.06M) of a 3% aqueous solution of mercuric chloride are added. under a nitrogen atmosphere with stirring to 272 g (41.7M) of zinc dust and the mixture is stirred for 5 minutes at room temperature. A suspension of 40 g (0.316 H) of 4,5-dihydro-9,10-dimethoxy-5-methyl-4-oxo-dibenz / cd, phenylindole in 544 ml of ethanol is added in the same way as 3400 ml of 2N hydrochloric acid. The reaction mixture is heated to 65 ° C and maintained at this temperature for 30 minutes. After adding 272 ml of 37% hydrochloric acid, the reaction mixture is stirred at 65 ° C for 16 hours. After cooling to 10 ° C, the suspension is filtered. The filtered zinc dust is washed with 1600 ml of a 1: 1 mixture of methylene chloride and ethanol. The filtrate is cooled in an ice bath, basified with 4 liters of concentrated NH 4 OH and extracted three times with methylene chloride (2000 ml each time). The combined organic phases are dried, filtered and evaporated to give (5aRS) -4,5,5a, 6-tetrahydro-9,10-dimethoxy-5-methyl-dibenz / cd, f / indole (m.p. 126-218 ° with decomposition). crystallized from ether). NMR 100 MHz (CDCl 3): δ 2.66 ppm (3H, sj N-CH 2), 4.2 δ (1H, d, 11Hz, C-40 ° H).

The starting material can be prepared as follows: a) A mixture of 860 ml (6116M) of trifluoroacetic anhydride and 860 ml (11.24 M) of trifluoroacetic acid is added to 140.0 g (0.380 M) of 8-bromine at room temperature under a nitrogen atmosphere. 3,4-Dimethoxy-phenanthrene-9-carboxylic acid and the mixture are stirred for 10 minutes. The resulting brown clear mixture is cooled to -5 ° and 30.4 g (0.468M) of sodium azide are carefully added in solid form. After stirring for 3 hours at 2 °, the reaction mixture is poured onto ice and the resulting suspension is filtered and washed with 1.4 liters of water. The crude white product is suspended in 2.5 l of ethanol and the reaction mixture is refluxed. After the addition of 1680 ml of 2N sodium hydroxide, the resulting yellow clear solution is refluxed for 45 minutes. The solution is cooled to room temperature> 7,0407, extracted with methylene chloride and the organic phase is dried and evaporated. The resulting 9-amino-8-bromo-3,4-dimethoxy-phenanthrene melts at 107-108 °.

b) 19.4 ml (0.346 H) of formic acid are added dropwise over 5 minutes to a suspension containing 64.5 g (0.397 H) of N, N-carbonyldiimidazole in 387 ml of absolute tetrahydrofuran and stirred for 30 minutes at room temperature. . This solution is added dropwise over 5 minutes at 0-3 ° to a solution of 100 g (0.301 M) of 9-amino-8-bromo-3,4-dimethoxyphenanthrene in 1600 ml of tetrahydrofuran, and the reaction mixture is stirred for 16 hours. . After cooling to -10 ° C, the mixture is filtered and the crystals are washed with ether and dried in vacuo. The resulting 8-bromo-9-formylamino-3,4-dimethoxyphenanthrene melts at 191-193 °.

c) 1000 ml (1.0M) of a molar solution of diobrane in tetrahydrofuran are added rapidly under a nitrogen atmosphere to a suspension containing 90 g (0.249 M) of 8-bromo-9-formylamino-3,4-dimethoxyphenanthrene in 900 ml of anhydrous tetrahydro-furan. The resulting solution is refluxed for 4 1/2 hours and then stirred at room temperature for 16 hours.

After cooling to -5 ° C, 1800 ml of 2N sodium hydroxide are added dropwise over 5 minutes. The reaction mixture is heated to reflux and the tetrahydrofuran is evaporated off under normal pressure. 900 ml of ethanol are added and evaporated off on a rotary evaporator. The addition of 900 ml of ethanol and evaporation are repeated twice more. 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 resulting oil is emulsified in about 500 ml of hot methanol and methylene chloride is added to form about 1 liter of solution. The methylene chloride is removed by heating on a rotary evaporator, however, ensuring that no two-phase formation occurs.

is 70407

The solution is cooled to -10 ° to give 8-bromo-9-methylamino-3,4-dimethoxy-phenanthrene; it melts 7 at 5-77 °.

d) 70 g (0.202 M) of 8-bromo-9-methylamino-3,4-dimethoxyphenanthrene are dissolved under nitrogen in 700 ml of anhydrous methylene chloride and 139 ml (0.808 M) of N-ethyldiisopropylamine and 38 ml of (0.404 M) ethyl chloroformate is 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 remaining ethyl chloroformate is removed by heating at 70 ° under vacuum. Crystallization from ether / petroleum ether gives 8-bromo-9- (N-ethoxycarbonyl-N-methyl) amino-3,4-dimethoxyphenanthrene. (Mp 100-110 °).

e) 101.8 ml (0.167 M) of a 1.64 molar solution of n-butyllithium in hexane are added over 10 minutes to a solution containing 70 g (0.167M) of 8-bromo-9- (N-ethoxycarbonyl-N-methyl) -amino -3,4-dimethoxy-phenanthrene in 1890 ml of tetrahydrofuran and 630 ml of n-hexane, which is 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 150 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-4-oxo-dibenz [cd] f-indole (m.p. 151-152 ° crystallized from ether / petroleum ether) .

Example 2

From the corresponding compounds of the formula IIIa, the following compounds of the formula II can be obtained in an analogous manner to Example 1: (5aRS) -5-ethyl-4,5,5a, 6'-tetrahydro-9β-dimethoxy-dibenz / cd. - indole (oil) NMR 60 MHz (CDCl 3): δ 4.40 ppm (1H, dd, 10 Hz and homoallyyl coupling 1Hz, C-4 * (H), 1.3 (3H, t, 7Hz, NCH 2 CH 3) 70407 (5aRS) -4,5,5a, 6-Tetrahydro-9,10-dimethoxy-Sn-propyl-dibenz [cd] indole (oil) NMR 60 MHz (CDCl3): <4 ", 40 ppm (1H, dd, 10Hz and homoallyy 1 coupling 1Hz, C-4 ekH) 1.00 (3H, t, 7Hz, NCH2CH2CH3).

The starting materials can be obtained as follows: a) 110 ml (0.638 M) of N-ethyldiisopropylamine are added to a solution of 100 g (0.302 M) of 9-amino-8-bromo-3,4-dimethoxyphenanthrene in 500 ml. of methylene chloride. A solution of 41.6 ml (0.585M) of acetyl chloride in 500 ml of methylene chloride is added dropwise over 20 minutes to this mixture. During the addition, the temperature of the reaction mixture is maintained at 20 ° with cooling in an ice bath. After stirring for 16 hours at room temperature, the mixture is poured into 2N hydrochloric acid and extracted with methylene chloride. The organic phase is washed with 2N sodium hydroxide solution and water, dried and evaporated to give 9-acetylamino-8-bromo-3,4-dimethoxy-phenanthrene (m.p. 200-202 ° crystallized from ether).

In an analogous manner, 8-bromo-3,4-dimethoxy-9-propionylamino-phenanthrene (m.p. 192-193 °) is obtained.

b) In an analogous manner to Examples ie) to le), the following compounds can be obtained: 5-ethyl-4,5-dihydro-9,10-dimethoxy-4-oxo-dibenz [cd, f] -indole (m.p. 125-126 °, decomposes), 4,5-dihydro-9,10-dimethoxy-4-oxo-5-n-propyl-dibenz / cd, β-indole (m.p. 103-105 °, dec.).

Example 3 5-Ethyl-4,5,5a, 6-tetrahydro-9,10-dimethoxy-4-methyl-dibenz [cd, f] indole (Compound of Formula II) a) 8-Bromo-9-ethylamino-3 1,4-dimethoxy-phenanthrene 9-Acetylamino-8-bromo-3,4-dimethoxy-phenanthrene is reduced using diborane in an analogous manner to Example 1e) to give 8-bromo-9-ethylamino-3,4-dimethoxy-phenanthrene. (M.p. 103-105 ° crystallized from ether).

h) 9- (N-Acetyl-N-ethyl) amino-8-bromo-3,4-dimethoxyphenanthrene 8-Bromo-9-ethylamino-3,4-dimethoxyphenanthrene is reacted in an analogous manner to acetyl chloride compared to Example 2a) 9 - (N-acetyl-N-ethyl) -amino-8-bromo-3,4-dimethoxy-phenanthrene. (M.p. 189 ° crystallized from ethyl acetate).

17 70407 c) (4RS) -5-ethyl-4,5-dihydro-4-hydroxy-9,10-dimethoxy-4-methyl-dibenzoindindole i) 10 ml (20 mM) of 2 molar tert-butyl A solution of lithium in pentane is added at -105 ° to a solution of 4.04 g (10 mM) of 9- (N-acetyl-N-ethyl) amino-8-bromo-3,4-dimethoxyphenanthrene in 130 ml. in anhydrous tetrahydrofuran and in 50 ml of n-hexane. The temperature of the reaction mixture is allowed to reach room temperature and the mixture is poured onto ice. After extraction with methylene chloride, the organic phase is washed with water, dried and evaporated. The obtained crude (4RS) -5-ethyl-4,5-dihydro-4-hydroxy-9,10-dimethoxy-4-methyl-dibenz [cd, f] indole in the form of a tan foam is further reacted immediately.

ii) 2.1 ml (3.3 mM) of a 5% solution of methyllithium in ether are added dropwise at -60 ° C to a solution containing 1 g (3.3 mM) of 4,5-dihydro-9,10-dimethoxy-5 -ethyl-4-oxo-dibenz (cd, N-indole (prepared in Example 2b)) in 30 ml of anhydrous tetrahydrofuran. The reaction mixture is allowed to reach room temperature and maintained at this temperature for 30 minutes. The mixture is basified with 2N sodium hydroxide solution and extracted with methylene chloride. The organic phase is dried and evaporated to give (4RS) -5-ethyl-4,5-dihydro-4-hydroxy-9,10-dimethoxy-4-methyldibenz [cd] indole as a dark green oil 1 H-spectrum (CHCl 3). ): 3550 cm (OH) / .The crude product is further processed immediately.

d) 5-Ethyl-9,10-dimethoxy-4-methyl-dibenz [cd, f} indolinium chloride 2 ml (10.5 mM) of a saturated ethereal hydrochloric acid solution are added to 3.2 g (10 mM) of crude (4 RS) -5-ethyl-4,5-dihydro-4-hydroxy-9,10-dimethoxy-4-methyl-dibenz [cd, f) indole dissolved in 30 ml of ether to precipitate a red product. After stirring for 30 minutes, the product is filtered to give 5-ethyl-9,10-dimethoxy-4-methyl-dibenz [4d] indolinium chloride, which is used immediately for the next reaction.

e) (4RS) -5-Ethyl-4,5-dihydro-9,10-dimethoxy-4-methyl-dibenz [cd,] indole 100 mg (0.33 mM) of 5-ethyl-9,10-dimethoxy-4- methyl dibenz / cd, N-indolinium chloride is added to a solution of 12.5 mg (0.33 mM) of sodium borohydride in 3 ml of anhydrous tetrahydrofuran and 3 ml of ethanol. After a vigorous 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 (4RS) -5-ethyl-4,5-dihydro-9,10-dimethoxy-4-methyl-dibenz / cd, f-indole as a green oil.

NMR δ 0 MHz (CDCl 3): δ 1.2 ppm (3H, t, 7Hz, NHC 2 CH), 1.49 (3H, d, 7Hz, C-4CH 3), 3.5 (2H, q, 7Hz, NCH CH), 4.88 (1H, q, 7Hz, C-4-H), 6.2 (1H, s, C-6-H), 8.98 (1H, d, 8Hz, C-1H).

IR (CH 2 Cl 2): 1635 cm -1 (> C = CN) f) 5-ethyl-4,5,5a, 6-tetrahydro-9,10-dimethyl-4-methyl-dibenz / cd, N-indole (according to formula II compound)

Reduction of (4RS) -5-ethyl-4,5-dihydro-9,10-dimethoxy-4-methyldibenz Zcd, E7indole in an analogous manner to Example 1 gives the title compound as a mixture of two racemates (oil). The individual racemates can be separated chromatographed on silica gel.

i) (+) - (4R *, 5aS *): NMR 100 MHz (CDCl 3): δ 1.4 2 (3H; d, 6Hz, C-4-q (-CH 3) ', ii) (+ _) - (4R *, 5aR *): NMR 100 MHz (CDCl 3): δ 1.18 (3H, d, 7Hz, C-4 ^ -CH 3)

Example 4

The following (4RS) -4,5-dihydro-9,10-dimethoxy-dibenz / cd, f-indoles of formula IIIb, wherein R1 and R2 are shown in the table, are prepared in an analogous manner to Examples 3a) -3e) from the appropriate starting materials (free of formula The bases according to IIIb are obtained as an oil with similar characteristic NMR data as described in Example 3e).

19 70407

Table I

Example R ^ i ch3 ch3 ii CH3 n-CgH ^ lii CH3 iso-C3H7 iv CH3 n-C ^ Hg v C2H5 CH3 vi n-C Η? CH2 vii iso-C3H7 CH3 viii n-C2Hg CH2 ix sec. "C ^ Hg CHg x tert.-C ^ Hg CHg xi n-CcH CH" was o xii -CH -CH2-CH3-CH3 CH3 CH3 ίΗ3

xiii -CH -C-CH CH

2 i o o ch3

xiv -CH-CH -CH „CH

t 2 o J

C2H5

xv -n-CrH CH

d 13 3 / CH2

xvi -CH CH

\ CH2 _______ i 20 70407

Compounds of formula IIIb can be directly converted to the corresponding 9,11-dimethoxy compounds of formula II in an analogous manner to Example 3b).

Example 5 4,5,5a, 6-Tetrahydro-9,10-dimethoxy-4, b-dimethyl-dibenz [cd, f] iridol (Compound of Formula II) a) (-) - (6aR) -5 1,6a, 7-Tetrahydro-10,11-dimethoxy-6,6-dimethyl-4H-dibenzoyl, 7-quinolinium iodide 100 ml (1.6 M) of methyl iodide are added to a solution containing 100 g (0.34 H) (-) - (6aR) -5,6,6a, 7-Tetrahydro-10,11-dimethoxy-6-methyl-UH-dibenzo [d] quinoline in 100 ml of methylene chloride and the mixture is refluxed for 30 minutes. On cooling, ether is added to the reaction mixture and the precipitate is filtered off and dried to give (-) - (6aR) -5,6,6a, 7-tetrahydro-10,11-dimethoxy-6,6-dimethyl-4H-dibenzo [e], g / quinolinium iodide (decomposes at 173-176 °).

b) (9RS) -9,10-Dihydro-3,4-dimethoxy-9-dimethylamino-8 "vinyl-phenanthrene 13.9 g (124 mM) of potassium tert-butylate are dissolved in 560 ml under a nitrogen atmosphere. tetrahydrofuran and 47 g (112 mM) of (-) - (6aR) -5,6,6a, 7-tetrahydro-10-11-dimethoxy-6,6-dimethyl-4H-di-benzoyl, quinolinium iodide The mixture is stirred at room temperature for 1 hour, poured onto ice and 560 ml of 10% hydrochloric acid are added, the mixture is washed with ether, the aqueous phase is neutralized with sodium bicarbonate, basified at pH 9 with 50 ml of 20% sodium hydroxide solution and extracted three times with methylene chloride. (500 ml each time) The combined methylene chloride extracts are dried and evaporated, and the residue is purified by chromatography on 1 kg of silica gel using ether as eluent to give (9RS) -9,10-dihydro-3,4-dimethoxy-9 -dimethylamino-8-vinyl-phenanthrene (m.p. 109 °).

c) (4RS) -4,5-Dihydro-9,10-dimethoxy-4,5-dimethyldibenz-Cdd> f) Indole 17.5 g (57 mM) of (9RS) -9,10-dihydro-3 1,4-Dimethoxy-9-dimethylamino-8-vinyl-phenanthrene is added to a stirred suspension of 10.2 g (57 mM) of N-bromosuccinimide in 55 ml of water. The reaction mixture becomes warm and after a few minutes the product precipitates. After about an 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-5,5-dimethyl-4-methylene-dibenzene. ? indolinium-2i 70407 bromide (sintered at 135 ° and melted at 165 °). The crude product is still processed immediately.

19.7 g (50.7 mM) of the indolinium bromide obtained in 100 ml of ethanolamine are stirred at 100 ° for one hour. The reaction mixture is poured onto ice / water and extracted three times with methylene chloride (300 ml each time). The combined methylene chloride extracts are dried and evaporated to give (4RS) -4,5-dihydro-9,10-dimethoxy-4,5-dimethyl-dibenz [cd, f] indole as an oil.

(4RS) -4,5-dihydro-9,10-dimethoxy-4,5-dimethyl-dibenz / cd, f? Indole can also be prepared as follows:

A solution of 2.7 g (0.86 ml *, 17 mM) of bromine in 15 ml of chloroform is added dropwise at room temperature to a solution containing 4.8 g (15.5 mM) of (9RS) -9.10 -dihydro-3,4-dimethoxy-9-dimethylamino-8-vinyl-phenanthrene in 45 ml of chloroform. After the reaction, the mixture is cooled in an ice bath. The resulting precipitate 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-5S-dimethyl-dibenz [cd]. indolinium bromide (sintered at 132 ° and melts at 154-158 °). The product is directly converted to (4RS) -4,5-dihydro-9,10-dimethoxy-4,5-dimethyl-dibenz [cd, f] indole by heating in ethanolamine as described above.

d) 4,5,5a, 6-Tetrahydro-9,10-dimethoxy-4,5-dimethyl-dibenz-β-indole (compound of formula II) 400 ml (44.2 mM) of 3% mercuric chloride the aqueous solution is added to 200 g (330 mM) of 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-dimethoxy-4,5-dimethyl-dibenz [f] indole in 400 ml of ethanol is added and the mixture is heated to 50 ° C. -60 °: in front for one hour. 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 off and the filtrate is basified 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-4,5-dimethyl-dibenzene. £ cd, f) 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 fractions of methylene chloride / methanol (98.5: 1.5) as eluent.

22 7 0 4 0 7

Fractions 125-240 contain (-) - (4R *, 5aS *) - 4,5,5a, 6-tetrahydro-9,10-dimethoxy-4,5-dimethyl-dibenz [cd, ij) indole in. NMR spectrum of the base (CDCl 3 90 MHz): δ fl, 44 ppm (3H, d, 6Hz, C-4) melting point of the corresponding hydrochloride: less than 185 ° (decomposes).

Fractions 250-330 contain (-) - (4R *, 5aR *) 4,5,5a, 6-tetrahydro-9,10-dimethoxy-4,5-dimethyl-dibenz [d, f] indole. NMR spectrum of the base (CDCl 3, 90 MHz): mp 1.24 ppm (3H, d, 7Hz, C 4 H 4 -CH 2) melting point of the corresponding hydrochloride: above 200 ° (decomposes).

Example S

In an analogous manner to Example 5, the following compounds of formula II can be prepared from suitable starting materials (free bases of compounds of formula II are obtained as an oil).

(i) (ί) - (4R *, 5aS *) - and (±) - (4R *, 5aR *) - 5-ethyl-4,5,5a, 6-tetrahydro-4-methyl-9,10- dimethoxy-dibenz cod,? indole; (ii) (-) - (4R *, 5aS *) - and (-) - (4R *, 5aR *) - 4,5,5a, 6-tetrahydro-4-methyl-5-n-propyl-9, 10-dimethoxy-dibenz {cd, f} indole; (iii) (-) - (4R *, 5aS *) - and (-) - (4R *, 5aR *) - 4,5,5a, 6-tetrahydro-4-methyl-5-isopropyl-9,10- dimethoxy i-dibenz {cd, f} indoles; (iv) (±) - (4R *, 5aS *) - and (-) - (4R *, 5aR *) - 5-n-butyl-4,5,5a, 6-tetrahydro-4-methyl-9, 10-dimethoxy idibenz {fcd, £> indole.

Example 7

Solution containing 5 g (18 mM) of (-) - (4R *, 5aS *) - 4,5,5a, 6-tetrahydro-9,10-dimethoxy-4,5-dimethyl-dibenz [bd] indole base in 10 ml of ethyl acetate and 0.5 ml of methanol are added to a solution of 3.3 g (22 mM) of (-) - tartaric acid in 22 ml of ethanol / ethyl acetate (1: 1) and the mixture is stirred for one hour. for a period of time at room temperature, after which (-) - (4S, 5aR) -4,5,5a, 6-tetrahydro-9,10-dimethoxy-4,5-dimethyldibenzene Zcd, f_7 indoline (-) -tartrate kitevtvi · Decomposition: 183-190; Mp (δp -120.6 ° (H 2 O) c = 0.5). The corresponding hydrochloride obtained in a known manner decomposed at 210-2 5 at 5 °; = -140 ° (H 2 O, c = 0.5).

The mother liquors remaining from the crystallization of the tartrate are basified with potassium carbonate and the mixture is extracted with methylene chloride. The combined organic extracts are washed neutral, dried and evaporated. The residue (about 2.5 g; 9 mM) is mixed with 1.65 g (11 mM) of (+) - tartaric acid in 11 ml of ethanol / ethyl acetate (1: 1).

23 70407

After stirring for 1 hour at room temperature, (+) - (4R, 5aS) -4,5,5a, 6-tetrahydro-9,10-dimethoxy-4,5-dimethyl-dibenzZ.cd, f.7- Λ Λ indole (+) - tartrate crystallized. Decomposition: 185-190 °; = + 116 ° (H 2 O, c = 0.5). The hydrochloride obtained in a known manner decomposed at 215-230 °; = + 140 ° (H 2 O, c = 0.5).

The following compounds can be obtained in an analogous manner from (+) - C4R *, 5aR *) - 4,5,5a, 6-tetrahydro-9,10-dimethoxy-4,5-dimethyl-dibenz / cd, f7indole (as free base): (+) - (4S, 5aS) -4,5,5a, 6-Tetrahydro-9,10-dimethoxy-4,5-dimethyl-dibenzZcd, f-indole (-) - tartrate: Decomposition: 177-18 °; [.alpha.] D @ 20 +116 (H 2 O, c = 0.5) Decomposition of the corresponding hydrochloride: 160-164 °; L = + 160 ° (H 2 O, c = 0.5) (-) - (4R, 5aR) -4,5,5a, 6-tetrahydro-9,10-dimethoxy-4,5-dimethyl-dibenzZgd, 7-indoline (+) - tartrate: Decomposition: 178-18 2 °; = -114 ° (H 2 O, c = 0.5). Decomposition of the corresponding hydrochloride: 158-162 °; = -156 ° (H 2 O, c = 0.5).

The following compounds can also be obtained in an analogous manner from (+) - (4R *, 5aS *) -5-ethyl-4,5,5a, 6-tetrahydro-9,10-dimethoxy-4-methyl-dibenzZcd, f7indole (free base () (+) - (4R, 5aS) -5-ethyl-4,5,5a, 6-tetrahydro-9,10-dimethoxy-4-methyl-dibenzZcd, E7-indole (-) - tartrate: = +96 ° (H 2 O, c = 0.5). The corresponding hydrochloride obtained in a known manner decomposes 18 at 5-188 ° = + 121 ° (H 2 O, c = 0.5).

(-) - (4S, 5aR) -5-ethyl-4,5,5a, 6-tetrahydro-9,10-dimethoxy-4-methyl-dibenz [cd] indole (+) -tartrate ', = - 103.4 ° (H 2 O, c = 0.5). The corresponding hydrochloride obtained in a known manner decomposed at 189-190 ° / ° C = -122 ° (HgO, c = 0.5).

Example 8 (-) - / HR *, 5aS *) - 4,5,5a, 6-Tetrahydro-9,10-dihydroxy-4,5-dimethyl-dibenzZdd, 17 indole (Compound of Formula I 16.8 g (53 .8 mM) (+) - (4R, 5aS *) - 4,5,5a, 6-tetrahydro-9,10-dimethoxy-4,5-dimethyl-dibenz [cd, f] indole is dissolved in 400 ml of 47% the aqueous hydrobromic acid solution and solution are heated for 3 hours at 130 DEG C. After evaporation the mixture 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 anhydrous hydrochloride decomposed at 100 DEG C.; (DMSO): δ 1.81 (3H, d, 5Hz, C-4 - ^ - CH 2) 24. Å _ 70407

Examples 9-39

In an analogous manner to Example 8 and using the corresponding starting materials, compounds of formula Ia can be obtained in which R 1 and R 2 are as shown in the following table.

Table II

Eg R, R »Configuration Decomposition ^ is" Σ'5 '---------------------------------- ----------------- q_e_Q * 52 __________ ------------------- I5 9 CH3 CH3 (-) - (4R * , 5aR *) 185 ° i) 10 CH »CH (-) - (4S, 5aR) 185 ° d / ---, 20 Q1o

Aou7d = -9 7 11 CH, CiU <+) - <4R, 5aS) 185θ1) + 96 ° 12 CH »CH (+) - (4S, 5aS) 215ol), - / 20 il3Co L <xJ ^ - + 136 13 CH CH (-) - (4R, 5aR) 205ol) & jl ° - -13 5 ° 14 CH »C Hr (-) - (4S, 5aR)> 280o2) = -6 5.7 ° 15 CH3 C2H5 ( -) - (4R *, 5aR *) 195θ1) 16 CH3 C2H5 (-) - (4R *, 5aS *) 190Ol) 17 CH3 n_C3H7 (“) - (4R *, 5aR *) 180Ol) 18 CH3 n-C3H7 C -) - (4R *, 5aS *) 180Ol) 19 CH3 iso-C3H? (-) - (4R *, 5aR *) 20Sol) 20 CH3 iso-C3H? (-) - (4R *, 5aS *) 220ol) 21 CH3 n_CHH9 (-) - (4R *, 5aR *) 160Ol) 22 CH3 n "C14H9 (-) - (4R *, 5aS *) 210Ol) 23 H CH3 (-) - (5aRS) 270-275o2) 24 H C2H5 (-) - (5aRS)> 240 ° 2) 25 H n_C3H7 (-) - (5aRS) 258-2601 ^ 26 C2H5 CH3 (-) - (4 R *, 5aR *)> 175 ° 2) 25 7 0 4 0 7

Table II (continued)

Eg Rn R „Configuration Decomposition 1 Z, 9 n Z * ^ 7 ^ u (H 2 O), __________________________________ c_r_Qa§) ________ 27 C2H5 CH3 (±) - (4R *, 5aS *)> 195o2) 28 iso-C3H? CH 3 (-) - (4R *, 5aR *)> 225 ° 2) 29 iso-CQH 7 CH 2 - (-) - (4R *, 5aS *)> 200 ° 2) 3/6 + o?) 30 n-CO 2 ~ CH- (-) - (4R *, 5aR *)> 215uz'3 7 3 2) 31 nC „H7 CH- (-) - (4R *, 5aS *)> 185uz '3 <3, o?) 32 tert.-CH CH3 (-) - (4R *, 5aR *) 284-285 33 tert.-C, H * CH- (-) - (4R *, 5aS *) 270-272 ° 2) 4 S 3 02 ) 34 sec. -C. Hq CH- (-) - (4R *, 5aR *) 263-265 ^ '^ ^ ^ xo 2) 35 sec.-C ^ Hg CH3 (-) - (4R *, 5aS *) 285-286UZ' 36 nC ^ Hg CH3 (±) - (4R *, 5aR *) 212o2) 37 nC ^ Hg CH3 (±) - (4R *, 5aS *) 269-271 ° 2)

CH

38 -CH "| 2 CH" (-) - (4R *, 5aR *) 170 ° 2) \ I 3 ch2

CH

39 -C.yC I 2 CH3 (-) - (4R *, 5a S *) 258-261 ° 2) XCHO 2 ': _! _ 1 - .. J__

Hydrochloride Hydrobromide 26 70407

Example 40 (-) - (4R *, 5aS *) - 9,10-Dibenzoyloxy-4,5,5a, 6-tetrahydro-4,5-dimethyl-dibenzZ.cd, E7indole (Compound of Formula 4 7.7 ml (40.6 mM) of benzoyl chloride are added to a solution of 1.3 g (4.31 mM) of (-) - (4R *, 5aS *) - 4,5,5a, 6-tetrahydro-9.10-dihydroxy -4,5-dimethyl-dibenz [Bd, f] indole hydrochloride in 12 ml of trifluoroacetic acid and the mixture is refluxed for 1 hour. The residue is purified by chromatography on a 165 g silica gel column using methylene chloride / methanol (97: 3) as eluent to give pure (-) - (4R *, 5aS *) - 9,10-dibenzoyloxy-4,5,5a, 6-tetrahydro -4,5-dimethyl-dibenz- [cd, f] indole The hydrochloride melts at 215-225 ° (decomposed) crystallized from ether / acetone, NMR 100 MHz (DMSO): d 1.39 ppm (3H, d, 6Hz, C -4oF (CH3).

Examples 41-105

In an analogous manner to Example 40 and using the corresponding starting materials, compounds of formula are obtained

Rlj-COO || ^ | kj-k J-N'R2 where R1, R2 and R2. Rg are shown in the following table.

27 7 0 4 0 7

Table III

"O r" Decomposition

Eg 1 2 3, 190,, [0,) 20 (c-05 S) Sacs' saxaattaac iBseaDaxessc: sssaasss2sss.'s = sss = r = cssss = cs = = a = = sr = = 41 H -CH3 _ ^ yci 1B9-191 ° 1) 7) 42 H -C2il5 "CH2" ^ 3165 ° 1, 7) 43 II -n-C3l7 "CH2" ^ 3 210-213 ° 1)?) 11 7) 44 II -nC -.il., -c H. 210-213 ° '' 3 f 2 b 45 -Cli3 "C2H5 -0-3 214-219 ° 2) 7) 46 -CH3" C2H5 -210-213 ° 2) 7) 47 -CH3 "c2H5 ~ 33" Br 232-239 ° 2) 7) 48 -CU3 -C2IIb _CH2 ^ 3 196-20ö ° 2) 7) 49 -CH3 - C2 '15 - 235-238 ° 4)? ) [a) 2 ° (NeOH) -32.8 ° 50 -CH 3 _C 2 H 5 -1H-Vd 221-223 ° 5) 7) [α] 2 ° (MeOH) + 2 8.4 ° 51 _CH 3 "n_C 3 H 7 ~ 33 158-169 ° 3) 7) / -CH2 52 -CH -nC H (CH \ I 205-212 ° 3)?) 3 3 7 ^ CH2 28 70407

Table III (continued) o η Ι7Ϊ Decomposition

For example, Ri r2 'R3 J [a.] 20 (c = 0.5) sssäbs ssssssaes' .lececsscas:: = sssss3ss = scs = = ^ = sr- .cass ^ = = a = = = rssssr: 53 -CH3 -n-C3M7 - (C..2) 3-C »3 155.161o3) 7) 54 -CU3 -n-C3„ 7 -C2H5 205-207 »3'7 '55' CH3 -CA -0--3 170-175 »2) 7 '^ och3 56 -CH -e,!., FU» 161-163 "5) 7) · 4 J \ / 39 () \ -4 [a] (NcOH) +18, 8 ° ÖCH 1 57 ~ CH 3 - C 215 - ^ ^ -Cl 17go 2) 7) 58 -CH 3 -C 2 15 5 -y 180-19O 2 -2) (T \> 188 ° 6) 7) 7) 59 -CH "COHr - (/ N > vn 3 2 JV = / [n] 20 (MeO11) -21.2 °

CE

60 "CH 3 -C 2 J 15 _ ^ yOCH 3 169-17 3 ° 2)?) 61" CH -C 1! hTV OCR 2424o'245 ° 5) 7) 3 2 5 \ _ / 3 [a] 2 (MeOH) + 26 ° 29 7 0 4 0 7

Table III (continued) ~~ I ΓΙΙ Decomposition

For example, R 1 N 3 is "1 1 J (" d 2 ° (c-0.5) 62 -CU 3 -C 2 H 5 -JT \ 198-200 "2'71

'- ^ - OCU

//%. 2 \ 1 \ 63 -CII3 -C2H5 ° / 203-205 °

Cil3 ° 64 -CH3 -CH3 (CH2 ^ 3 218-22 3 ° 2) 7) 65 -CH, -Cn3 X1) 221 · 2'7 »

3 CH

66 -CH, -CH 3 -Cl / I 213 ° 2) 7) ch 2 67 -CH 3 -CH 3 - (CH 2) 2 -CH 3 193-199 ° 2) 7) 68 -CH 3 -CU 3 -C 1 I 204 ° 2) 7 ) 69 "CH3 -n-C3l7 -iso-CH210 ° 3) 7) 70" CH13 -n-C3l7 201-207 ° 2) 7) 71 "CH3 -n-C3H7 -tert.-C2Hg 193 ~ 197 ° 2) 7) 72 -CH3 -n-C3-7-iso-C H 208 ° 2) 7) 73 -CH3 -C21I5 205-207 "2'7» 74 '"H -C2n5 -f \ -CH 2j ° “5) 7>

- U

* 30 70407

Table III (continued) τ-, · R, R ~ R "Decomposition

Es ™ · 1 2 3 W, f (c-0,5) x = ss * x ssseasact. ' -tsEtnaanaKsaacs: 'saessasasasessassa ^ r C3s = = = as = ea = s5sss 75 -CH, -C 11 f / \ 2) 7) 3 c2 5 —V Ί 206-208 °'] xcii3 76 -CIL -CH f / \ 2) 7) 3 2 5 \ _ / 194-196 ° ''

H 3C

77 'C "3 ~ C" 3 - <Q «B-nr3» 7' 78 CII3 "CH3 -tert.-C4119 206 ° 2) 7) 79 -C" 3 -C113 -iso-C3ll7 194-202 »2 »7 '80 -C1I3 -CH3 \ 215-235 ° 6) 7) M ^ ° (U20) -56o 81 -CIL -CIL · -iso-CJL · 215-225 ° 6) 7) $ $ J / 2n [ ra] D (H 2 O) "166 ° 82 -CH 3 -C 2 H 5 165-180 ° 2 ^ 7 5 83 -CH 3 -C 2 II 5 -180-195 ° 3) 7) 84 -CH 3 -C 2 H 5 - <Q> 2120221 ° '' - '(nDD (MeOH) + 12 ° 70407

Table III (continued) R R R. "Decomposition

Ex. 12 J [ot] 2U (c = 0.5): s3at: aacaascc: asBasrxcaas isssjssssssassaKnsss ^ = s = = s = 85 -CH, ~ C, H -tcrt.-CJL 170-185 ° 2) /) J λ b 4 y 86 -CH, -C? 11 -tert.-C 11 180 ° G) 7) 3 2 5 4 9 2o [aj ^ CMcoin-in.a0 87 -C113_C2H5 -tert.-C4U9 225- 235 ° 3) 7) 88 -CH3-C2H5. -iso-C3II7 135-150 ° 2) 7) 89 -CH. -C2llt. -iso-C3117 220-230 ° 3)?) 9 ° -CH3 -C2H5OCl3-136-142 ° 2.7) / T ~ \ 163-17l ° 6) 7) 91 "CH3" C2H5 "Cl, 2 ° (MeOH) -65.1 ° 92 -C113 -C2II5 -CH2-O) 136-142 ° 2) 7) OCCl3 93 -CII3 -C2H5 "C" 2 '<G> 133-140 “2) 7) CI13C> T-.

94 -CH3 -C2II5 -C1I2_ ^ A-C1 200-212 »2'7 '95 -CH, -CH ru /} λ 123-133” δ> 7) 3 2 5 -CHr <^ J) _cl [(t ) 20 {HuUll) _66) 2o 32 7 0 4 0 7

Table III (continued) R j, r "Decomposition

Eg 1 ^ 2 i, [o0 | j ° (C = 0.5) ΐ = κΐε ssacoBscc: Taanecnasa ::: asaucxE: 3Ss = aaz = = = = .. '.; j: r = i ;; - s = "= :: = = = = -r 96 -CII3 -C21] (. -CH2 ^ 199-203 ° 2)?) 97 -CH ^ _C2H5 15 4-161 ° 98 -CH -C Hr -CH - / "" Λ 136-142 ° 3 2 -> 2 y = / [<x] ^ l) (MeOU) -76.3 °

Cl C 1 · ν_ 99 -CH3 'c2115 -ai2- (V ~ \ 239-244 ° 2) 8) cr 100 -ch3 -c2m5 _c „2 _ ^> _ ci 187-] 91 ° 2) δ)

Cl 101 -CH3 _C2H5 -CH2-f ^ Cl 210-212 ° 2) 8) 102 -CH3 ~ C2Us 199-214 ° 2) 7) 33 7 0 4 0 7

Table III (continued) K Decomposition

Eg J [x] J0 (c = 0.5) 103 -CU3 -C2H5 18Ί -189 ° 2) 7) 104 -CH3 ~ C2H5 184-190 ° 2) 7)

F

105 -ch3 -ch3 -cn2 ~ ^ ~ \ 208-21.0 ° 6) 7) ~ [r,] * ° (MuOH) -72.7 ° 1) (-) (5aRS) 2) (-) (4R * , 5aS *) 3) (^) (4R *, 5aR *) 4) (-) (4R, 5aS) 5) (+) (4S / 5aR) 6) (-) (4S, 5aR) 7) Hydrochlorides 8) Methanesulfonate i

Claims (1)

A process for the preparation of novel therapeutically useful 4,5,5a, 6-tetrahydro-dibenzZ.cd, f7 indole derivatives of formula I wherein R 1 is hydrogen, (C 10) alkyl or (C 3-10) cycloalkyl, R 2 is (C 1-6 alkyl and R 1-4 substituents are the same and represent hydroxy or acyloxy of the formula R 0 -O-a optionally substituted alkyl; (C 3-6) cycloalkyl; or optionally substituted phenyl; and pharmaceutically acceptable acid addition salts thereof); characterized in that a) a compound of formula Ia OH wherein R 1 and R 2 have the same meaning as above is prepared by cleaving the ether groups Z from a compound of formula II z (P 1 KJkJ-n-r 2 <II) wherein R R 1 and R 2 are as defined above, and Z is a cleavable ether group, or b) a compound of formula Ib is prepared R 7 II I '(Ib) wherein R and R 0 are as defined above and the R' substituents 1. o are similar and significant acyloxy of the formula R-O-O-a wherein R is as defined above by acylation of a compound of formula Ia, and the resulting compound is recovered as the free base or a pharmaceutically acceptable acid addition salt. 36 70407 For the preparation of a compound, therapeutically active compound 4-, 5,5a, 6-tetrahydro-dibenzZcd, f7indolder with the formula I R3 R, JL Π R 3V = | or (C 3-7) cycloalkyl, R 2 is (C 1-4) alkyl and R substituents are identical to those of hydroxyl or acyloxy of formula R -C 0-0-a color Ra is optionally substituted alkyl; (C 3-7) cycloalkyl of; or optionally substituted with phenyl; the same pharmaceutical composition is given in the form of a composition, which means that a) framställer en förening med formuleln Ia X il "° y> rYVi - ^ - r2 <Ia) color R ^ och R2 betecknar samma som ovan, genom spjälkning av etergrupp for form II II Λ zvVyVri -N-R2