FI59096B - FOERFARANDE FOER FRAMSTAELLNING AV NYA VINKAMINDERIVAT ANVAENDBARA SAOSOM PSYKOSTIMULANTER - Google Patents

Description

ΪΙ3Ξ * 1 Γβΐ rtiv ANNOUNCEMENT rQnQ <«Π | m <") UTLÄGCNINGSSKRIFT 3 ^ 096 C The Patent Association has been shown 10 06 19-31

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Pfttanttl and Rakiatari Government .... ......... __. ., .., _ * (44) NlntivUulpunon j · kuLlullulwn pvm. -

Patana · och ragllfearttyralMn 'AmBkan utligd och utUkrlftvn pubiicund 27.02.8l (32) (33) (31) Eritty «uolkvui - Begird prlorltac 18.12.7 3 06.02.jb, 08.02.7 ^ Switzerland-Switzerland (CH) 17689/73, 1621 Ilb, u65 / Jb (71) Sandoz AG, Basel, Switzerland-Switzerland (CH) (72) Paul Pfäffli, Arlesheim, Switzerland-Switzerland (CH). (7M 0y Roister Ab (5 * 0 Method for the preparation of new vincamine derivatives for use as psychostimulants - Förfarande för framställning av nya vinkamin-derivat användbara s & som psykostimulanter

The invention relates to a process for the preparation of novel vincamine derivatives of the formula I which can be used as psychostimulants in their optically active forms or in the form of their racemates and acid addition salts,

Ri_19 I p I

Hoi •! CH 2 O 22 22 20 21 in which the formula represents a bromine, fluorine or chlorine atom or a hydroxyl, lower alkyl or previous alkoxy group, provided that R 1 in the 11 or 12 position may not be a methoxy group. The process is characterized in that a) compounds of the formula II, R1-Π? 12 I and 11 l CH3OCC (R20) C = CH; wherein R 1 is as defined above and R 2 is lower alkyl, is cleaved under acidic conditions and formed from compounds of formula I wherein R 1 is as defined above and compounds of formula III,

JCD

Wherein the mixture in the formula R 1 is as defined above, the mixture is separated in a known manner, or b) compounds of the formula XII in which R 1 is as defined above are treated at a temperature below 0 ° with hydrogen halide and the resulting reaction product is then hydrolysed, or c) in the preparation of a compound of formula 1 ',

rr A

A: »r 2 '2 HoJ' 2 ^ CH 300 C 22 20 21 59096 vincanine is brominated in its optically active form or racemate, then the possible racemates of the compounds of the formula I are separated, if desired, as their optically active antipodes and / or the compounds of the formula I thus obtained are converted to acid addition salts if desired.

The reaction according to process variant a) is carried out by reacting compounds of the formula II in which R1 and R1 'have the above-mentioned meaning with a hydrogen halide solution, e.g. methanolic hydrochloric acid solution, aqueous hydrogen iodide solution or hydrogen bromide solution at temperatures between 0 and 80 °, preferably a temperature between 10-60 °. The compounds of formulas I and III formed, in which R has the abovementioned meaning, can then be isolated from the reaction mixture and purified in a known manner.

The reaction according to process variant b) is carried out by reacting compounds of the formula III in which R has the abovementioned meaning at temperatures below 0 °, preferably between -20 and -150 °, with absolutely dry and halogen-free hydrogen halide. Suitable hydrogen halides are mainly hydrogen bromide, although hydrogen chloride or iodine are also useful. The solution is then evaporated to dryness, the residue is then slurried at temperatures below 0 °, preferably between -20 and -150 ° in a suitable non-freezing solvent such as acetone or tetrahydrofuran, followed by the addition of 0 °: below an antifreeze aqueous mixture of a solvent such as acetone or tetrahydrofuran, an organic base such as pyridine, sodium hydrogen carbonate or alkali hydroxide and water, preferably in a ratio of 70:20:10, and the mixture is warmed to room temperature.

The compound of formula I formed can then be isolated from the reaction mixture and purified in a known manner.

In the preparation of the compound of formula 1 ', the bromination of vincamine is carried out by known methods by coupling bromine to a benzene ring with ferric chloride or bromide, boron tribromide, zinc (II) chloride, aluminum chloride or iodine. The reaction may take place, for example, by suspending an optically active or racemic vincamine in a neutral solvent such as chloroform, chlorobenzene, methylene chloride by adding one of the above catalysts and then dropwise dropping a solution of bromine in a suspension at -20 to + 20 °. of the above-mentioned neutral solvents. The resulting compound of formula 1 'can then be isolated from the reaction mixture in a known manner and purified.

The free bases of the compounds of formula I can be converted into their acid addition salts in the customary manner and vice versa.

The hitherto unknown compounds of the formula II in which Rei and Railia have the abovementioned meaning are prepared by reacting the (S) -ethyl- [3- (p-toluenesulfonyloxy) -prop-1-yl] malonaldehyde acid ethyl ester-diethyl acetal of the formula IV CT "o With a tryptamine derivative according to V.

-r— CH? -CH.-NH- V

»I-t ΓΤ where R 1 represents the same as above, the compound of formula VI formed by melting, -Tno ^ Jk« J hn

^ \ VI

H W 5 (C H O) CH 5 wherein R 2 is as defined above in the presence of imidazole to give a compound of formula VII

The K ^ ^ K

'' '' S vakV

11 I J

(2E, .0) 2 C} i ^ T ^ K

5 59096 where R. | means the same as above. The latter compound is boiled in aqueous acetic acid to give a compound of formula VIII,

__(/"OF

R 'vm 4 jO

where means the same as above. Then the dimethyl-phosphono-alkoxy-acetic acid methyl ester of formula IX, Ϊ / 0¾

(CH 3 O) 2 P-CH. IX

NC00CH3 in which R2 represents a lower alkyl group is reacted in a neutral solvent such as 1,2-dimethoxyethane, tetrahydrofuran, dioxane, diethyl ether or dimethylformamide with a strongly basic condensing agent, e.g. an alkali metal hydride such as alkali metal hydride, in the presence of tert-butylate or sodium ethylate with a compound of formula VIII in which R1 is as defined above, the resulting mixture of Z and E isomers of the compound of formula X is isolated, h, -n χ

B

CH300C (R 20) C = CH

wherein R1 and R2 are as defined above, in a known manner from the reaction solution, after which the iscan mixture is chromatographically separated if desired and the Bischler-Napieralsk ring is then closed by dissolving the mixture in phosphorus oxychloride or polyphosphoric acid or a mixture of both, and boiling to a mixture of phosphorus oxychloride and polyphosphoric acid and a neutral solvent such as toluene, chlorobenzene or chloroform and heating for several hours at a temperature between 60 ° C and 120 ° C, after which the iminium salt of formula XI formed in a known manner is isolated from the reaction mixture.

N \ XI

B

CH_OOC (R 0) C = CH 2 13 2 where and have the same meaning as above. The iminium salt of general formula XI is then converted to perchlorate by shaking by precipitation with aqueous 10-sodium perchlorate solution or by partitioning the iminium salt between a methanolic solution of 10-sodium perchlorate and methylene chloride and then reducing.

The reduction is carried out either catalytically or in the presence of organometallic compounds. The catalytic reduction is preferably carried out in neutral solvents, such as methanol or ethanol, with the addition of a weak base, such as potassium acetate or triethylamine. The reaction is preferably carried out at room temperature and normal pressure. Among the common hydrogenation catalysts, palladium catalysts, especially supported ones, have proven to be good. Upon completion of the hydrogen bonding, the reaction mixture is further treated, e.g. by filtering off the catalyst, the enol ethers of the formula II formed, in which Rite and Rite have the above meaning and which are a mixture of Z and E isomers, are isolated from the filtrate in a known manner, purified and fractionated if desired. a chromatograph.

However, the reduction can also be carried out with organometallic compounds, preferably lithium aluminum hydride. The reduction is preferably carried out in a neutral solvent, preferably cyclic or open-chain ethers, such as, for example, tetrahydrofuran, dioxane, diethyl ether, diglyme or τ 59096 dibutyl ether. The reduction is preferably carried out at a temperature in the range of 0 ~ 80 °.

The complex compound formed in the reaction is then decomposed in a known manner, and the enol ethers of the formula II in which R 1 and R 1 have the above-mentioned meaning are isolated from the reaction mixture and purified.

The process according to the invention can be used both for the preparation of optically active forms of the compounds of the formula I and for the preparation of racemates.

Optically active compounds are obtained from optically active intermediates according to the process steps described above. If racemic intermediates are used, racemic end products are obtained; these or their precursors can then be separated into their optically active isomers in a known manner, e.g. by converting the racemic end products or their precursors with optically active bases or acids into a diastereoisomeric salt mixture and isolating the optical antipodes therefrom.

The compounds of the formula I, in their optically active forms, as well as in their racemates and acid addition salts, have interesting pharmacological properties and can be used as medicaments.

Compounds of similar structure to those prepared by the process of the invention are known from Tetrahedron 29 (1973) 1131 and Coll. Czech. Chem. Commun 29 (196H) UH7. However, no synthetic method of preparation or pharmacological properties have been reported for these naturally isolated alkaloids. It has now surprisingly been found that the compounds prepared by the process of the invention have a considerably better therapeutic effect compared to these known compounds of similar basic structure. To demonstrate the excellent therapeutic efficacy of the new compounds, pharmacological comparative experiments were performed with three compounds prepared by the method of the invention, namely 10-bromocincamine (10-BV), 11-bromo-vincamine (11-BV) and 10-fluorovincamine (10-FV) and the known vincamine ( V). The effect of the compounds on the rat sleep-wake cycle was determined by conventional methods as follows:

Male adult SPF-Wistar rats (UOO-S50 g) were used in the experiments. During the installation of the recording electrodes, the experimental animals were anesthetized with pentobarbital (Nembutal, 50 mg / kg, i.p.). The electrodes used to record the cortical electrical curve (ECoG) were permanently placed in the skull above the areas of the cerebral cortex that most affected visual and sensorimotor properties. An electrode placed above the cerebellum was used as a reference electrode. Muscle electric curve (EMG) was recorded from the neck muscle using a bipolar steel wire electrode. The ECQG electrodes, which were 8 59096 stainless steel screws (diameter 0.7 mm), and the EMG electrode were connected with a silver wire (diameter 0.3 mm) to a seven-pin contact (Winchester Electronics). The contact was attached to the skull with dental cement. Prior to registration, the animals were allowed to acclimate to the equipment for at least three weeks. Each experimental animal was housed in its own cage, where the light and dark times were controlled (light 700-1900 hours) at a temperature of 22-2 ° C.

ECoG and EMG curves were recorded using a 16-channel plotter (Grass Model 78) and two EEG-P plotters (Elema-Schönander Mingograph). The paper speed was 6 mm / s.

The cages in which the rats were kept at the time of registration were large plastic cylinders. The rats were able to move freely in them even when the electrodes used for registration were attached to them. Prior to registration, rats were allowed to acclimate to registration cages for three days. Registration times were six hours and recordings were always made during the light period of the light / dark cycle. Test compounds were administered to experimental animals 15 minutes before the start of the registration period. As a blank, the animals were administered a solvent containing no active compound one day before the test compounds were administered. The experiments examined the duration of wake, SWS and paradoxical sleep (= REM sleep), the average number of PS episodes (? (PS), and the length of time from the beginning of the registration period to the beginning of the first REM episode). (PS lat.) The percentage change (increase or decrease) caused by the test compounds compared to the results of the blank experiments is shown in the following table.

Dose Compound SWS% PS% nPS% PS lat. Wake 30 mg / kg 10-BV -U8 -81 * -81 + 27U e.t.

P '°' 11-BV -11 -87 -68 +182 +38 10-FV -28 -90 -81 +232 + U8 V -27 -69 -53 +160 +52 30 mg / kg 10-BV e.t. E.T. E.T. E.T. E.T.

1, p · 11-BV -U5 -91 -82 +227 +82 10-FV -23 -78 -69 +217 +37 V -17 -58 -UU +173 +32 e.t. = not studied 9 59096

In the following table, the results are reported by giving a value of 100 for vincamine and comparing the new compounds prepared by the process of the invention.

Dosage form Compound SWS PS nPS PS lat. Wake p.o. 10-BV 177 122 153 172 e.t.

11-BV 1 * 1 126 128 11U 73 * 10-FV 103 130 153 1 * + 5 92 i.p. 11-BV 263 157 187 130 260 * 10-FV 135 135 157 125 112

From the above results, it is found that 10- and 11-bromocincamine surprisingly significantly shortens all studied sleep phases (slow-wave sleep, paradoxical sleep, and paradoxical sleep latency) and reduces the average number of paradoxical sleep cycles compared to vincamine. The only exception is 11-bromocincamine when administered orally does not shorten the duration of slow-wave sleep as much as vincamine. (In this case, however, it must be taken into account that 11-bromocincamine administered intraperitoneally significantly shortens the duration of slow-wave sleep compared to vincamine).

From the above results, it is also found that 11-bromocinnamine and 10-fluorovincamine significantly prolong the waking period compared to vincamine. However, the same phenomenon is not observed when the active compound is administered orally to experimental animals.

Thus, 10- and 11-bromocincamine and 10-fluorovincamine have a much more effective effect on the sleep-wake cycle, especially the sleep cycle, than vincamine, and these compounds can be used more effectively than vincamine in the treatment of brain dysfunction.

In an experiment in mice, an increase in excitability was observed at doses ranging from 10 to 100 mg / kg p.o. The sleep phases of electroencephalograms in rats showed a decrease in sleep and an increase in wakefulness at doses ranging from 10 mg / kg to 30 mg / kg i.p. or p.o. Changes like this indicate an increase in insomnia and mental stimulation.

Due to their aforementioned effects, the compounds are particularly suitable in geriatrics for the treatment of arrest disorders due to cerebrovascular injury and cure, and for the treatment of disorders of consciousness due to skull injuries.

The dosage employed will, of course, vary with the substance employed, the mode of administration and the condition being treated. However, satisfactory results are generally obtained in animal experiments at a dose of 10-100 mg / kg. For larger mammals, the daily dose is about 1 to 500 mg. These doses may, if necessary, be administered in two or three divided doses containing 0.5 to 30 mg of a compound of formula I in combination with solid or liquid carriers or diluents, or as a retardant dose.

In the following examples, which further illustrate the invention, all temperatures are in degrees Celsius and are uncorrected.

The specific rotation angles of all optically active compounds have been measured in chloroform solution.

Example 1: (3S, 1US, 16S) -1Q-fluoro-vincamine and (3S, 16S) -10-fluoro-apovincamine to 3.86 g of a mixture of 3-ZT1S, 12bS) -1-ethyl-9 -fluoro-1,2,3,10,6,7,12,12b-octahydro-indolo [2,3 '% 7-quinolizin-1-yl] -2-methoxypropenoic acid methyl ester Z and E isomers, 10 ml of 33 The hydrogen bromide solution and the mixture are stirred under a nitrogen atmosphere for half an hour in a bath at 6 ° C. When the mixture is then evaporated to dryness, a foam forms. This is dried at 50 ° under a vacuum of 20 mm and ground. The residue is dissolved in 20 ml of methylene chloride, added dropwise with stirring to 20 ml of 2N ammonia at 0 °, the aqueous phase is separated, then extracted with 10 ml of methylene chloride, the first and then the second organic phase are washed with 20 ml of the same wash water, these are combined and dried over 3 g of sodium sulphate and evaporated to dryness at 30 ° under a vacuum of 20 mm. The residual brown foam is chromatographed on 100 g of silica gel (0.05-0.20 mm) and methylene chloride / methanol (99: 1) in a long, thin column and collecting the eluate eluted with the same solvent mixture in 100 ml fractions. Fractions 8-13 contain the major part, fractions 1U-30 of a minor portion of (3S, 16S) -10-fluoro-apovincamine, which can be crystallized from methanol. The following fractions 31-36 are eluted with methylene chloride / methanol (98: 2) and contain (3S, 1HS, 16S) -10-fluoro-vincamine.

(3S, 1 Us, 16S) -10-fluoro-vincamine:

Sp. 218 ° (dec.); r * Jv ° = (1 ** CHCl 3) MMR spectrum (CDCl 3, 100 MHz): 0.89 (T, 7Hz / H 3 C (21) / 3 H) 1.17-3, UU (M / 1UH) among them at 2.10 + 2.20 (AB, 15Hz / H2C (15)) 3.80 (S / H C00C (22) / 3H) 3.88 (S / HC (3) / 1H) U, 62 (S / HOC (U) / 1H / exchangeable) 6.66-7.20 (M / HC (9,11,12) / 3H) (3S, 16S) -10-fluoro-apovincamine:

Sp. 17U °; * + 155 ° (1%, CHCl 3) WMR spectrum (CDCl 3, 100 MHz): 1.01 (T, 7Hz / H 3 C (21) / 3) 1.22-3.53 (M / 12H) among 11 59096 at 1.91 (Q, 71 ^ / 1 ^ 0 (20)) 3.93 (S / H3COOC (22) / 3 H) 1 +, 11 (S / HC (3) / 1 h) 6, 11 * (S / HC (15) / 1H) 6.70-7.27 (M / HC (9,11,12) / 3H) 3-ZI1S, 12bS) -1-ethyl-9-fluoro-1, 2,3,6,6,7,12,12b-Octahydro-indolo (2,3-a) quinolizin-1-yl] -2-methoxy-propionic acid methyl ester is prepared as follows: a) (S) -3-Ethyl-3-diethoxymethyl -1-Z2- (5-Fluoro-indol-3-yl) -ethyl] -2-piperidone 100 mmol of crude (S) -ethyl [3- (p-toluenesulfonyloxy) -prop-1-yl] -malonaldehyde acid ethyl ester-diethyl acetal are dissolved in a bath. At 30 ° to 50 ml of dimethyl sulfoxide, a solution of 17.82 g of 5'-fluorotryptamine in 50 ml of dimethyl sulfoxide is slowly added with stirring and stirred for 16 hours at 30 °. 200 ml of 2N sodium carbonate solution and 100 ml of toluene are then added dropwise with stirring at 23 °. The resulting mixture is filtered and then washed with 50 ml of toluene. The aqueous phase of the filtrate is separated, then extracted with 50 ml of toluene and both toluene phases are washed successively with 200 ml of the same water / ethanol mixture (80:20). The combined toluene phases are mixed with 20 g of sodium sulphate, filtered and evaporated to dryness at 1 + 0 ° under a vacuum of 20 mm to leave crude (S) -2-ethyl-2-diethoxymethyl-5- [-] - as a yellow clear oil. (5-Fluoro-indol-3-yl) -ethylamino-7-pentanoic acid ethyl ester. The product thus obtained can be used in the reaction with imidazole without further purification.

This raw material is mixed with 100 g of imidazole. The mixture is melted at 100 ° and allowed to stand for 20 hours under a nitrogen atmosphere at 130 °. After cooling the reaction solution to 100 °, the melt is poured into 80 ml of 100 ° T toluene. Upon stirring, crystals begin to form in the cooled solution at 1 * 5 ° and it is a paste that can still be stirred at 0 °. To this is added, at 0 °, dropwise, with stirring and with efficient cooling, 300 ml of 6N hydrochloric acid. The aqueous phase is separated cold, then extracted with 50 ml of toluene and both toluene phases are washed with 100 ml of the same aqueous 2N ammonia solution. After evaporation to dryness, the combined toluene phases give (1 + 0 ° / 20 mm) a yellowish oil which is chromatographed on 50 parts of silica gel with a mixture of methylene chloride and methanol - 98: 2 - and 25 parts of fractions are collected. From the combined residues of fractions 8-10, white crystals are obtained from ethyl acetate / hexane (20:80) at 0 °. Sp. 101 °; [.Alpha.] D @ 20 = + 6.7 DEG C., CHCl3).

b) (S) -3-Ethyl-3-formyl-1- [2- (5-fluoroindol-3-yl) ethyl] -2-piperidone 39.05 g of (S) -3-ethyl-3-diethoxymethyl -1- (2- (5-fluoroindol-3-yl) ethyl) -2-piperidone is mixed with 80 ml of 99 ~ acetic acid and 20 ml of water.

The mixture is boiled under a nitrogen atmosphere for 1/2 hour. After cooling, the solvent 12 5 9096 is evaporated; to remove most of the water and acetic acid, the oily residue is then dissolved twice more in 50 ml portions of toluene and re-evaporated to dryness. After crystallization from a mixture of ethyl acetate and hexane (1: 2) at 0 °, brownish crystals are obtained.

Sp. 116 °; = 31.5 ° (1%, CHCl 3).

c) 3 - ((S) -3-ethyl-1- [2- (5-fluoroindol-3-yl) ethyl] -2-oxo-3-piperidyl) -2-methoxypropenoic acid methyl ester

To a suspension of 360 mg of sodium hydride in 10 ml of anhydrous tetrahydrofuran is added dropwise, at room temperature, 3.185 g of dimethylphosphonomethanoic acid methyl ester.

After stirring the reaction solution for 30 minutes at room temperature, a solution of 3.1 g of (S) -3-ethyl-3-formyl-N- [2- (5-fluoroindol-3-yl) - ethyl-2-piperidone in 10 ml of anhydrous tetrahydrofuran. The reaction mixture is then stirred for a further two hours at room temperature, poured onto ice and extracted with methylene chloride. The organic phases are dried and evaporated to dryness. A yellowish oil is obtained which is 3 - ((S) -3-ethyl-1- [2- (5-fluoroindol-3-yl) ethyl] -2-oxo-3-piperidyl) -2-methoxypropenoic acid methyl ester A mixture of Z and E isomers.

d) (S) -1-Ethyl-9-fluoro-1- (2-methoxy-2-methoxycarbonylvinyl) -2,3,6,6,7,12-hexahydro-1H-indole [2,3-a] Quinolizin-5-ium-perchlorate 1+, 025 g of 3 - ((S) -3-ethyl-1- [2- (5-fluoroindol-3-yl) ethyl] -2-oxo-3-piperidyl ) A mixture of the E and Z isomers of -2-methoxypropenoic acid methyl ester is dissolved in 5 ml of phosphorus oxychloride and boiled for 3 hours under a nitrogen atmosphere. The solution is then evaporated under a vacuum of 20 mm at 60 ° and then for 15 minutes at 60 ° under high vacuum. After dissolving the residue in 10 ml of chloroform, the evaporation is repeated in the same manner, leaving the crude iminium chloride as a tan foam. 20 g of silica gel (0.05-0.20 mm) are applied to the column with methylene chloride, the crude iminium chloride is dissolved at 30 ° in methylene chloride and applied to the column. It is then washed with methylene chloride until a clearly visible dark brown area almost reaches the outlet of the column (100-200 ml). It is then eluted with 120 ml of a mixture of methylene chloride and methanol (90:10) and this eluate is evaporated to a foam at 30 ° under a vacuum of 20 mm.

50 ml of a 10 to 10 solution of sodium perchlorate are first placed in water at 0 ° and a solution of the above-mentioned foam in 5 ml of methanol is added dropwise with stirring. The pale yellow portion is filtered at 0 °, washed twice with 20 ml of water and filtered off with suction. The residue is distilled in a 20 mm vacuum and 30 ° bath until a solution is formed. This is added dropwise at 0 ° to 50 ml of sodium perchlorate (10%), the precipitate is filtered cold, washed 13 times with 20 nl of water at 0 ° and sucked dry. It is then dried to give the title compound as a mixture of E and Z isomers * e) 3 - ((1S, 12bS) -1-ethyl-9 * fluoro-1,2,3,10,6,7,12b-octahydroindolo (2,3- and 7-quinolizin-1-yl) -2-netoxy-propenoic acid methyl ether (S) -1-ethyl-9-fluoro-1- (2-methoxy-2-methoxycarbonylvinyl) -2,3,6,6,7,7 A mixture of the E and Z isomers of 12-hexahydro-1H'-indolo [2,3 "i} quinolizine-5" iumperchlorate is dissolved in 10 ml of a mixture of methylene chloride and ethanol (80:20) at 30 ° and the solution is added to the prehydrated solvent. to a mixture of 982 mg of potassium acetate, 2 g of Pd-carbon (10%) and 8 ml of ethanol and 2 ml of water, the mixture is then hydrogenated at room temperature and normal pressure with stirring until the consumption of hydrogen after 8 modes of coupling is practically complete.

After filtration through Hyflo and washing of the precipitate with 20 ml of a mixture of methylene chloride and ethanol (80:20), the filtrate is evaporated to dryness at 30 ° under a vacuum of 20 mm, the residue is dissolved in 20 ml of methylene chloride, added 0 °: Pig 20 ml of 2N ammonia and shake. The organic phase is separated, then extracted with 10 ml of methylene chloride, the 1st and 2nd methylene chloride phases are washed with 20 ml of the same water, combined and dried over sodium sulfate. Evaporate to dryness at 30 ° under a vacuum of 20 mm, grind, dry under high vacuum and give a crude product as a crude product 3 - ((1S, 12bS) -1-ethyl-9-fluoro-1,2,3-1 *, 6 , 7 * 12,12b-octahydro-indolo [2,3-b] quinolizin-1-yl] -2-methoxy-propenoic acid methyl ester is a mixture of Z and E isomers.

Example 2: (3S, 1US, 16S) -10-fluoro-vincamine To 35 mg of (3S, 16S) -10-fluoro-apovincamine is condensed at -78 ° to 1 ml of absolutely dry and bromine-free hydrogen bromide. After stirring for 15 minutes at -78 °, the solution formed is evaporated to dryness under a vacuum of 20 mm and at -78 °, the reaction vessel is filled with dry nitrogen and the emptying and filling are repeated twice more.

The residue is first slurried at -78 ° in 5 ml of acetone, then 1.5 ml of 10N potassium hydroxide are added at -10 ° with vigorous stirring. the resulting slurry is stirred for 1 hour at -a0 ° and the mixture is neutralized by stirring with 1 g of solid carbon dioxide. The mixture is then shaken with a mixture of 20 ml of methylene chloride and 7 ml of 2N ammonia, the aqueous phase is then extracted with 10 ml of methylene chloride and each of the methylene chloride phases is washed successively with 5 ml of the same washing water, dried over sodium sulphate and evaporated to dryness.

The residue contains (3S, 11+ S, 16S) -10-fluoro-vincamine and, in addition, some (38,16S) -10-fluoro-apovincamine and (3S, 11R, 16s) -10-fluoro-11 * -nivin as by-products. - 111 59096 mines. Crystallization from toluene gives (3S, 1 * + S, 16C) -10-fluoro-vincamine having the properties indicated in Example 1.

By using (3R, 16R) -10-fluoro-apovincamine as a starting material in the same way, (3R, 11 + R, 16R) -10-fluoro-vincamine having the same properties as (3S, 11 + S, 16S) -10-fluorine is obtained -vincamine, in the opposite direction of rotation.

Using racemic 10-fluoro-apovincamine as a starting material in the same manner, racemic 10-fluoro-vincamine is obtained; mp. 230 ° (dec.).

Example 3: (3S, 16S) -10-methoxy-apovincamine, (3S, 16S) -10-hydroxy-apovincamine, (3S, 11 + S, 16S) -1Q-methoxy-vincamine and (3S, 11 + S, 16S) -10-hydroxy-vincamine to 3.985 g of 3 (11S, 12bS) -1-ethyl-9-methoxy-1,2,3,6,6,7,12,12b-octahydro-indolo [2 A mixture of the Z and E isomers of 3-α7-quinolizin-1-yl-2-methoxypropenoic acid methyl ester is added to 10 ml of a 33 "solution of hydrogen bromide in acetic acid and the mixture is stirred under a nitrogen atmosphere for half an hour in a 60 ° bath. Evaporation of the mixture to dryness then leaves a foamy substance. This is dried at 50 ° under a vacuum of 20 mm and ground. The residue is dissolved in 20 ml of methylene chloride, the solution is added dropwise to 20 ml of stirred 2N ammonia at 0 °, the aqueous phase is separated, then extracted with 10 ml of methylene chloride, the first and then the second organic phase are washed with 20 ml of the same washing water, combined, dried over 3 g of sodium sulphate and evaporated to dryness at 30 ° under a vacuum of 20 mm. The residual brown foam is chromatographed on 100 g of silica gel (0.05 ~ 0.20 mm) supplemented with a mixture of methylene chloride and methanol (96: 1+) in a long thin column and recovered in 100 ml fractions eluting with methylene chloride. is 1 + -10% methanol.

The products elute in the following order: a mixture of methylene chloride and methanol (96: 1+) (3S, 16S) -10-methoxy-apovincamine, followed by (3S, li + S, 16s) -10-methoxy-vincamine; with a mixture of methylene chloride and methanol (90:10) (3S, 16s) -10-hydroxy-apovincamine, followed by (3S, 1US, 16S) -10-hydroxy-vincamine.

(3S, 16S) -10-methoxy-apovincamine can be crystallized as hydrobromide from isopropyl alcohol, (3S, 16S) -10-hydroxy-apovincamine as base from toluene.

15 59096 (3S, 16S) -10-matoxy-apovincamine 3p. (hydrobromide) = 235 ° (dec.); (base) = + 109 ° (0.25 L, CHCl 3).

HMR spectrum (CDCl 3, 100 MHz): 1.02 (T T Hz / H 3 C (21) / 3 H); 1.20 - 3.1 * 1 + (M / 12 H); among them at 1.92 (Q, 7 Hz / H2C (20)) \ 3.85 (3 / H C-O-C (10) / 3 H) ·, 3.93 (3 / H3C00C (22) / 3 H) ; U, 13 (S / HC (3) / 1H) and 6.10 (S / HC (15) / 1H); 6.78 (4.9 + 3 Hz / HC (II) 1H); 6.91 (D, 3 Hz / HC (9) / 1H); 7.13 (D, 9 Hz / HC (12) / 1H); (3S, l6s) -10-hydroxy-apovinkamiini

Sp. = 226 ° (dec.) I = + 121 ° (0.25 L, CHCl 3).

HMR spectrum (CDCl 3, 100 MHz): 1.00 (T, 7 Hz / H C (21) / 3 H); 1.23 - 3.51 (M 12 H); among them at 1.92 (Q, 7 Hz / H2C (20)) i 3.92 (S / H3C00C (22) / 3 H) and 1 +, 16 (S / HC (3) / 1H); about 6 (br. S / HO-C (10), exchangeable / 1H); 6.07 (3 / HC (15) / 1H); 6.68 (Q, 9 + 2 Hz / HC (II) / 1H) and 6.83 (D, 2 Hz / HC (9) / 1H); 7.07 (D, 9 Hz / HC (12) / 1H); (3S, 11 + S, 16s) -10-methoxy-vinc amine M.p. 160 ° ·, + 16.2 ° (0.3 δ, CHCl 3) HMR spectrum (CDCl 3> 100 MHz): 0.90 (T, 7 Hz / HC (21) / 3 H); 1.12 - 3.1 * 3 (M / 11 * H); among 2.09 + 2.20 (AB, 10 Hz Hz / HgC (15)); 3.80 + 3.82 (2 3 / H 2 -O-CUO) + Η3 <300 (22) / 6 Η) ς 3.88 (S / HC (3) / 1H); 1 *, 6θ (3 / H0-C (11 *), interchangeable / 1H); 6.72 (¾ 9 + 3 Hz / HC (II) / 1H); 6.86 - 7.20 (M / HC (9) + HC (12) / 2 H); 16 59096 (33,11 »S, 16S) -10-hydroxy-vincamine

Sp. (hydrogen fumarate) * 207 ° (dec.); (base) = + 25.1 ° (0.25%, CHCl 3).

NMR Spectrum (CDCl 3> 100 MHz): 0.89 (T, 7 Hz / H 3 C (21) / 3 H); 1.1U - 3.51 (M / 1 * »H); among them at 2.11 + 2.21 (Ad, 1¾ Hz / HgCl 2 S)) i 3.82 (S / H 3 C 20 C (22) / 3 H); 3.93 (S / HC (3) / 1H); about U.7 (br. S / H0-C (10) + HO-C (lU), exchangeable / 2 H); 6.6 ° (Q, 9 + 3 Hz / HC (II) / 1H); 6.77 - 7.03 (M / HC (9) + HC (12) / 21).

The starting material used is 3 - (β, 1S, 12bS) -1-ethyl-9-methoxy-1,2,3,1 », 6,7,12,12b-> octahydro-indolo [2,3-b] quinolizin-1- Yyl 47-2'-methoxypropenoic acid methyl ether is prepared as follows: a) (s) -3-Ethyl-3-formyl-1- [2- (5-methoxyindol-3-yl) -ethyl] -2-piperidone 100 mmol of crude (S ) -ethyl- (p-toluenesulfonyloxy) -prop-1-yl-7-malonaldehyde acid ethyl ester diethyl acetal is dissolved in 50 ml of dimethyl sulfoxide at 30 °, a solution of 19.02 g of 5-methoxy-tryptamine in 50 ml is slowly added with stirring. in dimethyl sulfoxide and stirred for 16 hours at 30 °. 200 ml of 2N sodium carbonate solution and 100 ml of toluene are then added dropwise with stirring at 23 °. The resulting mixture is filtered and then washed with 50 ml of toluene. The aqueous phase of the filtrate is separated, then extracted with 50 ml of toluene and both toluene phases are washed successively with 200 ml of the same water / ethanol (80:20) mixture. The combined toluene phases are mixed with 20 g of sodium ulphate, filtered and evaporated to dryness at 1 ° C under a vacuum of 20 mm to leave crude (S) -2-ethyl-2-diethoxyethyl-5'-2- as a brown oil. (5-metokei-indole-3'-yl) -pentanoic acid ethyl--etyyliaming7. The product thus obtained can be used in the reaction with imidazole without further purification.

This raw material is mixed with 100 g of imidazole. The mixture is melted at 100 ° and allowed to stand for 20 hours under a nitrogen atmosphere at 130 °. After cooling the reaction solution to 100 °, the melt is poured into 80 ml of 100 ° toluene. Upon stirring, the cooled solution begins to form crystals at 1 ° 5 ° and is still a stirrable paste at 0 °. To this is added 300 ml of 6N hydrochloric acid at 0 DEG and dropwise with stirring and efficient cooling. The aqueous phase is separated cold, then extracted with 50 ml of toluene and each toluene phase is washed with 100 ml of the same 2N of 17,59096 aqueous ammonia solution. The combined toluene phases give a brown oil after evaporation to dryness at 20 ° C under a vacuum of 20 mm.

This oil is mixed with 80 ml of 99% acetic acid and 20 ml of water. The mixture is boiled under a nitrogen atmosphere for 1/2 hour. After cooling, the solvent is evaporated off; to remove most of the water and acetic acid, the oily residue is then dissolved twice more in 50 ml of toluene and re-evaporated to dryness.

Roughly chromatograph on 10 parts of silica gel (0.05-0.20 mm) with methylene chloride / methanol 98: 2, corresponding to five parts, fractions 5-12 give a yellow oil which can be crystallized from a mixture of ethyl acetate and hexane = 3 : 7 at 0 °. (S) -3-Ethyl-3-formyl-1- {2- (5-methoxyindol-3-yl) ethyl] -2-piperidone is obtained as white crystals.

Sp. = 108 °; = - 2U, 3 ° (1 *, CHCl 3).

b) 3 - ((S) -3-ethyl-1- [2- (5-methoxyindol-3-yl) ethyl] -2-oxo-3-piperidyl) -2-methoxypropenoic acid methyl ester

To a suspension of 30 mg of sodium hydride in 10 ml of anhydrous tetrahydrofuran is added dropwise 3.15 g of dimethylphosphonomethoxyacetic acid methyl ester at room temperature, protected from moisture.

After stirring the reaction solution at room temperature for 30 minutes, a solution of 3.28 μg of (S) -3-ethyl-3-fornyl-N- [5- (5-n-e-toxoindol-3-yl) is added dropwise. ethyl E2-2-piperidone dissolved in 10 ml of anhydrous tetrahydrofuran. The reaction mixture is then stirred for a further two hours at room temperature, poured onto ice and extracted with methylene chloride. The organic phases are dried and evaporated to dryness. A yellowish oil is obtained which is 3 - ((S) -3-ethyl-1- (2- (5-methoxyindol-3-yl) ethyl) -2-oxo-3-piperidyl) -2-methoxypropene a mixture of the Z and E isomers of the acid methyl ester.

c) (S) -1-Ethyl-9-methoxy- (2-methoxy-2-netoxycarbonylvinyl) -2,3,6,6,7,12-hexahydro-ΙΗ-indole-3,3-g? quinolizine-5-ium-perchlorate 4.1 g of 5 - ((S) -3-ethyl-1- [4- (5-methoxyindol-3-yl) ethyl] -2-oxo-3- A mixture of the Z and E isomers of piperidyl) -2-methoxypropenoic acid methyl ether is treated in the same manner as in Example Id to give a mixture of isomers of the above title compound.

d) 3-ZlIS, 12bS) -1-Ethyl-9-methoxy-1,2,3,1 ', 6,7,12,12b-oftahydroindolo [2-quinolizin-1-yl] -2-methoxypropenoic acid methyl ester (3) - 1-ethyl-9 "methoxy-1- (2'-methoxy-2-methoxycarbonylvinyl) -2,3,1 +, 6,7,12-hexahydro-1H-indolo [1,3-d] quinolizine-5- A mixture of 18-9096 E and Z isoesters of ium perchlorate is treated according to Example 1e to give 3 - [(1S, 12bS) -1-ethyl-9-methoxy-1,2,3,6,6,7,7 A mixture of the Z and E isomers of N, N-methoxypropenoic acid methyl ester of? 2-octahydro-indolo-N, N-methoxypropenoic acid methyl ester.

Example U: (3S, 1US, 16S) -10-methoxy-vincamine To Μ7Λ mg of (3S, 16s) -10-methoxy-apovincamine hydrobromide is condensed at -78 ° to 1 ml of absolutely dry and bromine-free hydrogen bromide. After stirring for 15 minutes at -78 °, the resulting solution is evaporated to dryness under a vacuum of 20 mm and at -7 °, the reaction vessel is filled with dry nitrogen and the draining and filling are repeated twice more.

The residue is first slurried at -78 [deg.] C. in 5 ml of acetone, then 1.5 ml of 10 [mu] l of hydroxide are added effectively with stirring at -1 [deg.] C., the resulting slurry is stirred for 1 hour at -10 [deg.] C. and neutralized with stirring with 1 g of solid carbon dioxide. Then shake with 20 ml of methylene chloride and with 7 ml of 2N ammonia, the aqueous phases are then extracted with 10 ml of methylene chloride and each of the methylene chloride phases is washed successively with 5 ml of the same washing water, dried over sodium sulphate and evaporated to dryness.

The residue contains (3S, 16S) -10-methoxy-vincamine and, as a by-product, some (3S, 16S) -10-methoxy-apovincamine and (3S, 11 * R, 16S) -10-methoxy-LU-epivincamine. Crystallization from isopropyl alcohol gives (3S, lkS, 16S) -10-methoxyvincamine having the values reported in Example 3.

By using (3R, 16R) -10-methoxy-apovincamine as a starting material in the same way, (3R, 1R, 16R) -10-methoxy-vincamine having the same properties as (3S, 14S, 16S) -10-methoxy-vincamine is obtained. , however, with the angle of rotation reversed.

By using racemic 10-methoxy-apovincamine as a starting material, racemic 10-methoxy-vincamine is similarly obtained; mp. 230 ° (dec.).

Example 5: (3S, 1 L, 16S) -10-Hydroxy-vincamine 357 .mu.l of (3S, 16S) -10-hydroxy-apovincamine are condensed at -78 ° to give 1 ml of absolutely dry and bromine-free hydrogen bromide. After stirring for 15 minutes at -7 ° C, the resulting solution is evaporated to dryness at a pressure of 20 mm and 78 °, the reaction vessel is filled with dry nitrogen and the emptying and filling are repeated twice more.

The residue is first slurried at -78 ° in 5 ml of acetone at -78 °, then 1.5 ml of 10 μl of potassium hydroxide are added with efficient stirring at -U0 °, the slurry formed is stirred for one hour at -U0 ° and neutralized by stirring. With 1 g of solid carbon dioxide. Then shake with 20 ml of methylene chloride and with 7 ml of 2N ammonia, extract the aqueous phase with 10 ml of methylene chloride and wash each of the methylene chloride phases successively with 5 ml of the same washing water, dry over sodium sulphate and evaporate to dryness.

The residue contains (3S, lUs, 16S) -10-hydroxy-vincamine and, in addition, (3S, lUR, 16S) -10-hydroxy-l-epivincamine as by-products. Crystallization from isopropyl alcohol in the presence of fumaric acid gives (3S, 1US, 16S) -10-hydroxyvinamine hydrogen fumarate as crystals having the properties reported in Example 3. By using (3R, 16R) -10-hydroxy-apovincamine as a starting material in the same way, (3R, 10a, 16R) -10-hydroxyvincamine having the same properties as (3S, 1US, 16s) -10-hydroxyvincamine is obtained, however the opposite.

By using racemic 10-hydroxy-apovincamine as a starting material in the same manner, racemic 10-hydroxyvincamine is obtained; mp. 230 ° (dec.)

Example 6: (3S, IUs, 16S) -10-chromium-vincamine IU, 19 g of (3S, lUs, 16S) -vincamine and 10.8 l of ferric chloride hexahydrate were suspended at 0 ° in 80 ml of chloroform and added dropwise. with stirring * 1 ml of a 1 molar solution of bromine in chloroform. After stirring for a further half hour at 0 °, 120 ml of 2N ammonia were added, the rust-brown precipitate was filtered off, the broth phases were separated, the aqueous phases were then extracted with 10 ml of methylene chloride, the organic phases were washed with water, combined, dried over sodium sulphate and dried over sodium sulphate. .

Upon dissolution of the residue in 80 ml of isopropyl alcohol, spontaneous crystallization occurred. These (3S, IUs, 16S) -11-bromo-vincamine crude crystals were isolated at 0 °. Pure (3S, IUs, 16S) -11-bromoquincamine was obtained by chromatography of the crude crystals on silica gel using methylene chloride / methanol (98: 2) as the solvent and then crystallizing from isopropyl alcohol.

Sp. 21 ° C (dec.); = + 8.7 ° (1% γ CHCl 3) NMR Spectrum (CDCl 3, 100 MHz): 0.86 (T, 7 Hz / H 3 C (21) / 3H); 1.18 - IM (M / 1H); among about 2.07 + 2.16 (AB, 15Hz / HgC (15); 3.80 (about S / H3C00C (22) + HC (3) / UH); U, 63 (S / HO-C ( 1U), exchangeable (1H), 7.0U - 7.7 (M / HC (9 + 10 + 12) / 3H).

By using racemic vincamine as a starting material in the same manner, racemic 11-bromo-vincamine is obtained; mp. 230 ° (dec.).

20 59096

Example 7: (3S, 1 ^ S, 165) -9 * fluoro-vincamine 35 μl of 1 + mg-.a (33.163) -9 "fluoro-apovincamine was condensed at -78 ° to 1 ml of absolutely dry and bromine-free After stirring for 15 minutes at -78 °, the resulting solution was evaporated to dryness under a vacuum of 20 torr and to dryness at kuiv78 ° and the residue was dried under these conditions for 16 hours.

The residue was first slurried at -7 ° C in 5 ml of acetone having a temperature of -78 °, after which 1.5 ml of 10 N aqueous potassium hydroxide solution was added effectively at -10 ° C with stirring, and the resulting slurry was further stirred for 1 hour. U0 °, neutralized with stirring with 1 g of solid carbon dioxide, shaken with 20 nl of methylene chloride and 7 ml of 2N ammonia, the aqueous phase is then extracted with 10 ml of methylene chloride, the organic phases are washed with water, dried over sodium sulfate and evaporated to dryness. .

The residue contains (33,11H, 16S) -9-fluoro-vincamine and, in addition, slightly (33,106) -9-fluoro-apovincamine and (33, lto, 16S) -9-fluoro-11 * -nivin- albumin. Crystallization from toluene gave (3S, 11 »S, 165) -9-fluoro-vincamine.

Sp. 210 ° (dec.); = + 6.0 ° (1 Jt, CHCl 3) NMR spectrum (CDCl 3, 100 MHz): 0.88 (T, 7 Hz / HC (21) / 3 H) δ 1.18 - 3.50 (M / li »H); among about 2.09 + 2.17 (AB, 13 Hz / H 2c (15)) i at 3.23 (H 2 C (6)) -, 3.79 (S / H 3 C 10 C (22) / 3 H); 3.86 (S / HC (3) / 1H); U, 6U (3 / H0-C (li *), exchangeable / 1H); 6.57 - 7.20 (M / HC (10 + 11 + 12) / 3 H); By using (3R, 16R) -9-fluoro-apovincamine as a starting material in the same manner, (3R, 11 + R, 16R) -9-fluoro-vincamine having the same properties as (3S, lUS, 16S) -9-fluoro-vincamine is obtained however, the opposite is true.

Example 8: (3S, 10a, 16s) -11-chloro-vincamine

By giving 3 - ((T, S, 12bS) -1-ethyl-10-chloro-1,2,3β, 6,7,12,12b-octahydro-indolo [2,3-b] quinolizin-1-yl] -2 A mixture of the Z and E isomers of methoxypropenoic acid methyl ester is reacted with hydrogen bromide in acetic acid as in Example 1 to give (SS.lUs.lSSj-11-chloro-vincamine).

Sp. 222 ° (dec. H β + 1.7 ° (0.1 %% CHCl 3) 21 59096 NMR spectrum (CDCl 3 t 100 MHz): δ, δΤ (Τ, 7 Hz / Η C (21) / 3 H); 1.08-3.3 U6 (M / 1U H); among them at 2.07 + 2.17 (AB, lk Hz / H ,, C (15)); 3.78 (S / H3C00C (22)) and 3.32 (shoulder / 1IC (3) / together 1 H), 4.55 (broad / H0-C (IU) »exchangeable / 1H) and 6.9 ^ -7.7 (M / ilC ( 9 + 10 + 12) / 3 11).

Example 9: (3S.1½, 16S) -9-hydroxy-vincamine

By giving 3 "(1S, 12bS) -1-ethyl-8-hydroxy-1,2,3,6,6,7,12,12b-octahydro-indolo [2,3-b] quinolizin-1-yl] -2 -methoxypropenoic acid methyl ester Z- and E-13 isomers react according to Example 1 with hydrogen bromide in acetic acid to give (3S, LUS, 16S) -9 * hydroxyvincamine, m.p. 220 ° (dec.) after crystallization from methylene chloride; Δ ° (1 *, CHCl 3) 1 H NMR Spectrum (CDSOCD ^ 100 MHz): 0.83 (T 7 Hz / H 3 C (21) / 3 H); 1.02 - 3.1 * 0 (M / p H ), at 2.13 + 2.21 (AB, 15 Hz / 11.0, 15 (15)), at 3.10 (S / H 2 C (6)), 3.67 (S / H C 20 C (22)) (3 H), 3.71 (3 [mu] C (3) / 1H) and 5.69 (S / 1/2 CH2Cl2 / 1 II), 6.3 U (D, 7 Hz / HC (10) / 1H) 6.50 (D, 8 Hz / HC (12) / 1H), 6.60 (S / HO-C (1U), interchangeable / 1H), 6.73 (about T, 8 + 7 Hz) / HC (II) / 1H); 9 »06 (S / H0-C (9), interchangeable / 1H);

Example 10: (3S, 1HS, 16s) -12-methyl-vincamine

By giving 3 (1S, 12bS) -1-ethyl-11-methyl-1,2,3,6,6,7,12,12b-octahydroindolo [2,3,3] quinolizin-1-yl] reaction of a mixture of Z and E isomers of methoxypropenoic acid methyl ester with hydrogen bromide in acetic acid according to Example 1 gives (3S, 11 * S, 16s) -12-methyl-vincemine, mp 22h ° (dec); = + 7.6 ° (1 2, CHCl 3).

22 59096 HMR spectrum (CDCl 3, 90 MHz): 0.89 (T, 7Hz / H C (21) / 7 H) and 1.13 - 3.13 (M / 17 H); among them at 2.00 + 2.19 (A3.11 Hz / HOC (15)); at 2.17 (S / CH C (12)); 3.81 (3 / H3C00C (22) / 3 11); 3.86 (S / HC (3) / 1H) ·, 3.99 (S / KO-C (II), exchangeable / 1H); 6.82 - 7.11 (M / 11C (9 + 10 + 11) / 3 H).

)

Claims (3)

23 59096 Claim: Process for the preparation of new vincamine derivatives of the formula I for use as psychostimulants in their optically active forms or as racemates and acid addition salts, R - or a chlorine atom or a hydroxyl, lower alkyl or former alkoxy group, provided that R1 cannot have a methoxy group at the 11- or 12-position, characterized in that a) compounds of the formula II, if ^ i - hu / w CH 00C (R 0) C = CH 2 | wherein Rg is as defined above and Rg is lower alkyl, cleaved under acidic conditions and formed from compounds of formula I wherein is as defined above and compounds of formula III, T 1 111 ch ^ 2.1.59096 wherein above, the mixture is separated in a known manner, or b) compounds of formula III in which R1 is as defined above are treated with hydrogen halide at a temperature below 0 ° and the resulting reaction product is then hydrolysed, or c) in the preparation of a compound of formula I ', 6 ____ 10. V "JJ: Br / T <3 '" N''V'J' & i HQv [iU J 16 18 CH3 ° o (r 22 21 vincamine is brominated in its optically active form or as a racemate, followed by possible racemates of the compounds of the formula I if desired, being divided into their optically active antipodes and / or the compounds of the formula I thus obtained are, if desired, converted into their acid addition salts. I --- jh 5 UJ1 JL in 12. N l 1 HO. , 1 3 19 ^ JiU ji 6 18 '^ 20 1 CH 00C / U i --_ J 21 color betyder en bromine, fluorine or chlorine or hydroxyl, alkyl alkyl or alkoxy group, color dock R ^ i 11- or 12- selected from the group consisting of methoxy groups, selected from the group consisting of a) compounds of formulas II, XX-XX B1 - ^ 12; I II JT 2 3 ^ CH3OC (R20) C = CH2O color in the form of a mixture, and R anhydrous in the alkyl group, in which the mixture is formed, in the form of a mixture with the formula I, color R ^ in the form of a mixture with the formula III, XX________ and CH 300C