SE448459B - 4A, 9B-TRANS-HEXAHYDRO-GAMMA CARBOL COMPOUNDS AS INTERMEDIATES FOR THE PREPARATION OF HEXAHYDRO-GAMMA CARBOL COMPOUNDS - Google Patents

Description

In the presence of platinum, it is expected that they are in the cis-position because it is a well-known fact that by means of said process hydrogen atoms in the cis-position are introduced into the carbon-carbon double bond. The listed compounds are neuroleptic and can be used to treat schizophrenia.

U.S. Pat. No. 3,991,199 discloses hexahydropyrimido [4,3-h] indoles useful as analgesics and sedatives, some of which are of interest as tranquilizers, some as muscle relaxants, and several exhibit hypotensive activity. The compounds are stated to fall under formula I and pharmaceutically acceptable salts thereof, in which formula the hydrogen atoms on the carbon atoms ha and 9b are in trans relationship to each other. When in the above formula Ya is -H, Xa represents -H, fCl, -Br, -CH 3, -t-CAH 9 or -OCH 3; and when Ya is -CF3, Xa represents -H. Furthermore, in the above formula, Ra represents hydrogen, 3-chloro-2-butenyl; Z-bromoallyl; benzyl; a benzyl ring substituted with methyl, methoxy or chlorine; phenethyl; 3-phenylpropyl; a 3-phenylpropyl ring substituted with chlorine, bromine or methoxy; fur- I furyl; 2-phenyl; alkyl of 1-5 carbon atoms; alkenyl having 3-5 carbon atoms; alkynyl of 3-5 carbon atoms; cinnamyl; a cinnamyl ring substituted with chlorine, bromine or methoxy; 3-phenyl-2-propynyl; cycloalkyl having 3-7 carbon atoms; cycloalkylmethyl having 4-8 carbon atoms; (methylcyclopropyl) -methyl; (cis-2,3-dimethylcyclopropyl) -methyl; cycloalkenylmethyl having 6-8 carbon atoms; cycloalkadienylmethyl having 6-8 carbon atoms; (2,3-448,459.-3-dimethylcycloprop-2-en-1-yl) methyl; exo-7-norcarylmethyl; (cis-1,6-dimethylendo-3-norcaren-7-yl) methyl; (4-methylbicyclo [2.2.2] oct-1-yl) methyl; (bicyclol.2.2] hept-2-yl) -methyl; (bicyclo [2.2.Z] hept-Z-en-5-yl) -methyl; 1-adamantylmethyl; or 2-adamantylmethyl.

The recently published Belgian patent 845 368 (Derwent No. O0043Y) discloses 5-phenyl-hexahydro-, 5-carbolines optionally substituted in the 2- and 4-positions with methyl or ethyl and in the 3-position with alkyl having 1- 3 carbon atoms, allyl or propargyl. They are useful as antidepressants.

In a recently published West German Offenlegungsschrift with no. 2 631 836, Derwent No. O9738Y, describes structurally related octahydropyrido ['', 3 ': 2,3] indolo [1,7-ab] flfbenzazepines which fall under the above formula, wherein Ya is an ethylene bridge between the two benzene rings Xa is hydrogen and Ra is CH 2 CH 2 COCH 3 or -CH CH COCGH 2 Z 5 'and tranquilizers. They are stated to be useful as analgesics. U.S. Pat. No. 2,026,263 discloses tranquilizers, namely 5-aryl-1,2,3 , 4-tetrahydro- ¥ -carboline with the formula X§ \\ víç: ~ \\] «'__ fl ___ /, /” \\ N_Rb [\ e | ll I \ / \ N / \ / fn \ ./ b / Z where Xb b has the same meaning as given below for R in the formula I. 'in 1 and Z? can represent hydrogen or fluorine and R 448 459 _4_ It has now surprisingly been found that trans-2,3,4,4a, 9b-hexahydro-1H-pyrido [[, 3-h] indoles according to the Swedish patent 7803625-8 has a markedly superior tranquilizing effect in comparison with the corresponding 1,2,3,4-tetrahydro-X-carbolines.

The tranquilizers according to Swedish patent 7803625 ~ 8 are i.a. enantiomeric and racemic compounds of the formula ° "": 3 Z X-rel // ñ 9b / \ N _ (gcHzhfly / Get 1 II l4a I \ :::: // and pharmaceutically acceptable salts thereof, in which formula the hydrogen atoms bonded to the carbon atoms in positions ha and 9b are in trans relationship to each other, and X1 and Y1 represent mutually identical or different substituents, namely hydrogen or fluorine; n is 3 or 4; m is 0 OH -ë- or -ëH and Z1 is hydrogen, fluorine or methoxy.

Additional compounds according to Swedish patent 7803625-8 have the formula according to Q 15 - 448 459 and pharmaceutically acceptable salts thereof, in which formula the hydrogen atoms bonded to the carbon atoms in the position and 9b are in the same trans ratio to each other as in formula II above; X1 and Y1 have the meanings given above; m is 2 or 3; and Z 2 is fluoro or methoxy.

The present invention relates to novel intermediates of the formula (X) specified in the claim for the preparation of the compounds according to Swedish patent 7803625-8.

The following reaction scheme illustrates the process by which the intermediates (X) of the present invention can be synthesized. _ \ X N-Rg (I) Bflg / ether \ 4 \ || 9b / \ N-Rz .___..___> &, / \\ N (2) H + \ _ / \ N / Iï I I sv sa.

(VIII) (IX) x (xx) in mco c H "¿\ ______ / \ NH (mon, cznsou / Hzo š / fi k N / | \ / 1 ß š \ iw (X) For economic reasons, R2 preferably represents benzyl , but R 2 may also represent other substituents for the purpose, as will be apparent to those skilled in the art.

L !! 448 459 _6_ The intermediate (X) is the subject of this invention.

The reduction of the tetrahydro-X-carbolines VIII to 4a, 9b-trans-hexahydro compounds IX is carried out in ether, usually tetrahydrofuran. To ensure complete reduction, a molar excess of borane / tetrahydrofuran complex (BH.THF) is usually used and a 100-200% molar excess of said complex is preferred. Although the reaction can be carried out at a temperature between -10 ° C and + 80 ° C, a temperature between 0 ° C and 65 ° C is preferred. Usually a solution of the starting material VIII in tetrahydrofuran is added to an ice-cooled solution of BH3.THF. After the addition is complete, the reaction mixture is heated to reflux and maintained at this temperature for between about 1 and about 2 hours or longer. The reaction is usually carried out in the presence of an inert gas, for example nitrogen. When the reaction is substantially complete, the solvent is evaporated and the residue is acidified with excess acid, for example hydrochloric acid in excess of Z-12 molar. A preferred acidifier is a mixture of equal volumes of acetic acid and 5M-HCl. The acidified mixture is usually heated under reflux for 1-2 hours or longer. The desired product can then be isolated, for example by evaporation of any residual ether and a portion of the acidic mixture and the precipitated product filtered off and washed. According to an alternative isolation method, the product (XI) is filtered off after the reaction mixture is boiled for the indicated time under reflux, the filtrate is cooled and made alkaline by adding, for example, sodium hydroxide, potassium hydroxide or sodium carbonate. The basic mixture is extracted with a water-immiscible organic solvent, for example chlorine, methylene chloride or benzene, the extracts are evaporated and the residue is purified by chromatography on a silica gel column and eluting, for example with ethyl acetate or a mixture of hexane and ethyl acetate.

By reducing tetrahydro-Y-carbolines with BH 3 .THF and subsequent acid treatment, hexahydro-X-carbolines are obtained, in which the hydrogen atoms bonded to the carbon atoms. _ ___ _ .. t ....._._...., _.._._.-._._ .., .._.___._.,, 448 459 ._7- i positions 4a and 9b are in trans relation to each other, see for example U.S. Pat. No. 3,991,199.

Thereafter, the 2-benzyl compounds IX are converted to the corresponding 2-hydrogen compounds X. In general, this can be accomplished by treating the compound IX with a lower alkyl-chloroformic acid ester in molar excess, for example methyl, ethyl, propyl or isobutyl ester. in the presence of a suitable reaction-inert organic solvent, which treatment is accompanied by alkaline hydrolysis. Preferred chloroformic acid ester is ethyl chloroformate due to its readiness and efficiency. By the term "suitable reaction-inert organic solvent" is meant a solvent which substantially dissolves the reactants under the reaction conditions without forming by-products. Examples of such solvents are aromatic hydrocarbons such as benzene, toluene and xylene; chlorinated hydrocarbons such as chlorophone and 1,2-dichloroethane; diethyl ünunrid dimethyl ether and dimethyl sulfoxide. An especially preferred solvent is toluene.

To the mixture of the starting material IX in said organic solvents inert to the reaction is added the chloroformic acid ester in an up to 10 molar excess. For economic reasons, a molar excess of between 3 and about 5 is preferred. The resulting mixture is then heated at a temperature of 80 DEG and 150 DEG C., typically at the temperature at which the mixture boils under reflux, for between 6 and 24 hours. hours or longer. Usually, for convenience, the reflux is carried out during the night. The reaction mixture is then evaporated in vacuo and the residue is taken up in a mixture of alcohol and water, whereupon an alkali, for example sodium hydroxide or potassium hydroxide, is added in a 10-30 molar excess based on the amount of starting material IX, whereupon the mixture thus obtained is heated under reflux, in typical cases all night. The solvent is then evaporated and the residue is partitioned between water and a water-immiscible organic solvent, for example chloroform, methylene chloride or ethyl ether, and the organic phase is evaporated to dryness. The evaporation residue, namely product X, can be used as such or subjected to further purification in accordance with standard procedures known in the industrial area in question, for example by column chromatography on silica gel.

Compounds IX, in which both X and Y represent hydrogen and R 2 benzyl, can be converted to the corresponding compound X by catalytic debenzylation using hydrogen and a catalyst consisting of palladium on carbon. The reaction is typically carried out using the hydrochloride of compound IX at a temperature of between 50 and 10,000, preferably 60-75 ° C, and a hydrogen pressure of between 140 and 690 kPa in the presence of a reaction-inert solvent, for example methanol , ethanol, isopropanol, ethyl acetate or mixtures thereof with water. When the hydrogen uptake is complete, the catalyst and the hydrochloride of the product, namely compound X, are precipitated by the addition of a non-solvent, for example ethyl ether, benzene or hexane. Alternatively, the free base X can be isolated by evaporating the filtrate from the debenzylation to dryness, partitioning the residue between an alkaline aqueous solution, for example an aqueous solution of sodium hydroxide, and a solvent such as chloroform or ethyl ether. The free base is then isolated according to standard methods, for example one of those described above.

The free bases X can serve as a precursor for the compounds VI in the manner shown in the following reaction scheme, in which X, Y, Z and n have the meanings given above: SEK! 448 459 _9_ oo Z ~ 'É- (cH) - ÉoH 0 0 = "Xï / 2 n-1 _Å \ /, I / \ NéïwH) _g / \> z (xm): Au vv X fi / / \ QH ß The acylation of the compounds X to the intermediates XIII can be effected using acids XII or the corresponding acid chlorides or acid bromides........................................ When acids XII are used in the acylation, approximately equimolar amounts of the acid and the compound X are brought into contact with each other in the presence of an inert reaction solvent, organic solvent and certain known condensing agents to form peptide bonds, such carbodiimides as e.g. dicyclohexylcarbodiimide and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, and alkoxyacetylenes, for example methoxyacetylene and ethoxyacetylene Preferred condensing agents are dicyclohexylcarbodiimide. the reaction with satisfactory results k is carried out at a temperature between -10 and + 50 ° C, it is preferred to apply a temperature between 0 and BOOC. At this temperature, the reaction is usually completed in a few hours. The product XIII 448 459 _10 .. is isolated, for example by filtration to remove insoluble matter and evaporate the filtrate. The product thus obtained usually has such purity that it can be used in the subsequent step.

Intermediate XIII is then reacted with lithium aluminum hydride. The product VI is also isolated in the manner indicated above and purified, for example by column chromatography on silica gel.

An alternative method for the preparation of 4a, 9b trans compounds VI in admixture with the corresponding dihydrated compounds VII is shown in the following reaction scheme: r- (CH2) n - (, 3H (1) BH3 / ether> (2 ) H + X / \ i% N- (cH2) m-cH = cH (V1) + \ ^ N f) f.

~ \ / KL ”(v11) Z \\ In the above formulas, X, Y, Z, n and m have the meanings given. The reaction with borane in ether, preferably tetrahydrofuran, and subsequent treatment with acid by? were carried out under the conditions set forth above for the preparation of the 2-benzyl compounds IX. Products VI 448 459 _11 .. and VII are separated, for example by column chromatography on silica gel.

The quantity ratio between products VI and VII depends on the amount of acid, for example hydrochloric acid, and the time for refluxing after the reduction with BH3.THF. Larger amounts of acid and longer reflux times favor the dihydrated product VII, whereas smaller amounts of acid and shorter reflux times favor the formation of product VI.

The compounds VI can also serve as precursors for the free bases X. In this case, for example, ethyl chloroformate is used, whereupon alkaline hydrolysis is carried out in the manner indicated above for pre-benzylation of the compounds IX in which R 2 is benzyl, so that the free bases X

The oxidation of the compounds VI using such reactants and the application of such conditions, which are known to selectively convert secondary alcohols to the corresponding ketones, gives the compounds of the formula xvi Z 1: / W /; u- (cnz) n- ë - <\:> í \ N / \\\ I | (XIV) see where X, Y, Z and n have the meanings given above. Examples of oxidizing agents that can be used in this reaction are potassium permanganate, potassium dichromate and chromium trioxide, the latter being preferred in the presence of pyridine. When carrying out this reaction with the preferred reactant, the starting alcohol VI is added to a reaction-inert solvent, for example, dichloromethane, chloroform or benzene, to a mixture containing chromium trioxide in up to 448,459 molar excess and pyridine in equal large molar excess of the stirred mixture, usually at room temperature, until the reaction is substantially complete. Usually between 15 * minutes and 1 hour is enough. The product is isolated, for example by filtering off the insoluble material, extracting the filtrate with a dilute aqueous solution of alkali, for example sodium hydroxide, drying the organic phase and evaporating it to dryness. The evaporation residue can, if. if desired, further purified, for example by column chromatography.

Preparation of starting materials: 2-Benzyl-5-phenyl-1,2,3,4-tetrahydro-γ-carboline is prepared by the Fischer indole synthesis using N, N-diphenylhydrazine and N-benzyl-4-piperidone. The mono- or difluoro-substituted tetrahydro-α-carbolines VIII, where at least one of X and Y represents fluorine and R 2 benzyl, used as starting materials are prepared from the corresponding compounds VIII, in which R 2 represents hydrogen, by reaction with a benzyl halide, e.g. benzyl bromide, in equimolar amounts.

The required compounds VIII (R2 = H) are prepared in the manner set forth in U.S. Patent No. 4,001,263.

The starting materials tetrahydro-Y-carbolines V are described in the same patent specification.

The other starting materials are either commercially available or their preparation is described in the chemical literature. They can also be prepared according to known procedures. Thus, for example, the phenylhydrazines are commercially available or synthesized by reduction of the phenyldiazonium salt as indicated by Wagner and Zook in "Synthetic Organic Chemistry", John Wiley & Sons, New York, N.Y., 1956, Chapter 26; the 1-substituted 4-piperidones are commercially available reactants or are prepared according to McElvain and Rorig, J. Am.

Chem. Soc., 70, 1826 (1948); the required 3-benzoyl-propionic acids and 4-benzoyl-butyric acids are either commercially available or prepared according to a modification of the "Organic Synthesis" procedure, Coll. Vol. 2, John Wiley and Sons, New York , NY 1943, P. 81.

The following examples illustrate the invention.

Example 1, dl-trans-2-benzyl-2,3,4,4a, 5,9b-hexahydro-5-phenyl-1H-pyrido [1,3-b] indole hydrochloride.

A three-necked round-bottomed flask equipped with a magnetic stirrer, thermometer, condenser and dropping funnel was charged with a solution of 0.140 mol of borane in 150 ml of tetrahydrofuran and the solution was kept at 0 ° C with stirring and under a nitrogen atmosphere. To the solution was added a solution of 23.9 g (0.07 l mol) of z-benzyl-5-phenyl-1,2,3A-teurahydropyridophase-bindol in 460 ml of dry tetrahydrofuran. The addition was carried out at such a rate that the reaction temperature was kept below 9 ° C.

When the addition was complete, the mixture was heated to reflux temperature and maintained at this for one hour. The solvent was evaporated in vacuo to give a white solid which was slurried in 40 ml of dry tetrahydrofuran, whereupon the slurry was heated, initially slowly, then the reaction mixture was added with 180 ml of a mixture (1 .mu.l) of acetic acid. and 5N-HCl. The suspension thus obtained was heated under reflux for one hour, after which it was cooled. Evaporation of the tetrahydrofuran and part of the acetic acid resulted in the precipitation of a white solid, which was filtered off and washed with water. The solid was reslurried in tetrahydrofuran, filtered off, washed with ethyl ether and air dried to give 16.7 g (63%) of the desired trans isomer, m.p.

Evaporation of the mother liquor gave an additional 7.2 g of product.

When the procedure described above was repeated but using the suitably substituted 2-benzyl-5-phenyl-1,2,4,4-tetrahydropyridol fl, 3-bindole as starting material the following 4a was obtained in the same manner. 9b trans compounds in the form of their hydrochlorides. * 1.ft 4a N-CH2C6H5 \ N \ w / .å Y Ä I Ä IH p-fluoro H o-fluorine FHF m-fluorine F p-fluorine F o-fluorine Example 2: dl-trans-5-phenyl -2,3,4,4a, 5,9b-hexahydro-1H-pyrido-1β-bindole.

A suspension of 4.17 g of dl-trans-2-benzyl-5-phenyl-2,3,4,4a-, 9b-hexahydro-1H-pyrido [α, 3-b] indole hydrochloride in 150 ml of absolute ethanol was hydrogenated at 345 kPa and 60-7000 using 1.0 g of a 10% Pd / C catalyst over 2 hours. The catalyst was filtered off and the filtrate was added with a sufficient amount of ethyl ether to precipitate the hydrochloride of the desired product, 2.76 g (87%) having a melting point of 235-237 ° C.

The hydrochloride was converted to the free base by partitioning between ether and a dilute sodium hydroxide solution. The ether phase was dried over sodium sulphate and evaporated to give the title compound of the present example in 97% yield and melting point 74-16 ° C.

Example Gel 3: dl-trans-8-fluoro-5- (p-fluorophenyl) -2- [α-hydroxy-4- (p-fluorophenyl) butyl] -2,3,4,4a, 5,9b- hexahydro-1H-pyrido [N, 3-b] -indole hydrochloride and dl-trans-8-fluoro-5- (p-fluorophenyl) -2- [N- (p-fluorophenyl) -3-butenyl] -2 , 3,4, & a, 5,9b-hexahydro-1H-pyrido [,, 3-b] indole hydrochloride. 448 459 _15 ..

In a 1000 ml reactor equipped with a magnetic stirrer and dropping funnel, a nitrogen atmosphere was maintained and 177 ml of 0.94 molar borane was charged to tetrahydrofuran. The solution was cooled in an ice bath and the cold solution was added over a minute with a solution of 25 g (0.0555 mol) of 8-fluoro-5- (p-fluorophenyl) -2- [α-hydroxy-4- (p- fluorophenyl) butyl] -2,3,4,5-tetrahydropyrido [β, 3-b] indole in 295 ml of tetrahydrofuran. The mixture thus obtained was stirred at room temperature for minutes, after which it was heated to reflux for 2 hours. The reaction mixture was cooled and evaporated in vacuo to give a liquid residue.

This was added with a mixture of 50 ml of acetic acid and 50 ml of SN-HCl, after which a strong gas evolution took place. The mixture was heated at reflux temperature for one hour, cooled to room temperature and filtered.

The filtrate was cooled in ice and made alkaline by adding a 50% (w / w) sodium hydroxide solution. The basic mixture was extracted with chloroform (2 x 150 ml), the combined organic phases were dried over magnesium sulphate and evaporated to dryness in vacuo to give a solid yellow foam (25 g). By thin layer chromatography on silica gel using a solvent system consisting of hexane and ethyl acetate in a volume ratio of 1: 1, the product was found to consist of 2 components. The foam was chromatographed on a column of silica gel and the elution was carried out with a mixture of hexane and ethyl acetate in a volume ratio of 1: 1 and the fractions were monitored by thin layer chromatography.

The fractions containing only the product, which moved faster, ie. 8-fluoro-5- (p-fluorophenyl) -2- [α- (p-fluorophenyl) -3-butenyl] -2,3,4,4a, 5,9b-hexahydro-1H-pyrido [α, 3-b] -indole was evaporated to dryness and taken up in acetone, whereupon it was converted into the hydrochloride by adding anhydrous HCl to acetone. The solid thus obtained was filtered off and dried, yielding 1.5 g of 3 -butenyl- compound with a melting point of 270-27300.

The fractions containing only the product which moved more slowly, namely 8-fluoro-5- (p-fluorophenyl) -2- [α-hydroxy-4- (p-fluorophenyl) butyl] -2,3,4, 4a, 5,9b-hexahydro-1H-pyridofA, 3-hindol was concentrated, taken up in ethyl ether and converted to the hydrochloride by the addition of anhydrous anhydrous HCl to give 10.8 g of this product, m.p. 24500.

The content of the faster-moving product, namely the 3-butenyl compound, was increased to 100% by suitably increasing the acidity and heating time at reflux in the mixture of acetic acid and hydrochloric acid.

Example SA: When the procedure described in Example 3 was repeated but starting from 8-fluoro-5- (o-fluorophenyl) -2- [N-hydroxy-4- (p-fluorophenyl) butyl] -2,3,4,5 -tetrahydropyridolβ, 3-indole, the faster-moving product was identified as trans-8-fluoro-5- (O-fluorophenyl) -2- [N- (p-fluorophenyl) -3-butenyl] -2,3, 4,4a, 5,9b-hexahydro-1H-pyrido [4,3-h] indole and it had a melting point of 141-14200. The slower product was identified as trans-8-fluoro-5- (o-fluorophenyl) -2- [α-hydroxy-4- (p-fluorophenyl) butyl] -Z, 3,4-4a , 5,9b-hexahydro-1H-pyrido [β, 3-bphindole and had a melting point of 195-19700.

Example 4: dl-trans-8-fluoro-5- (p-fluorophenyl) -2,3,4,4a, 5,9b-hexahydro-1H-pyridola, 3-bindole.

A. To a solution of 5.6 g (1.2 mmol) of dl-trans-8-fluoro- (p-fluorophenyl) -2- [α-hydroxy-4- (p-fluorophenyl) butyl] -2, 3.3 ml (4α, 5,9b-hexahydro-1H-pyrido [α, 3-b] indole in 10 ml of toluene were added 5.3 ml (55.7 mmol) of ethyl chloroformate. The mixture thus obtained was refluxed overnight and then evaporated to dryness to give a rubber which remained as an evaporation. This was added with 200 ml of a mixture of ethanol and water in a volume ratio of 9: 1. After the gum was dissolved, 15 g of potassium hydroxide were added and the mixture thus obtained was refluxed overnight. The solvent was evaporated in vacuo and the residue partitioned between water and chloroform. The organic extracts were washed with water, dried over sodium sulfate and evaporated to dryness. The oil obtained as an evaporation residue was taken up in ethyl acetate and the solution was passed through a silica gel column, which was first eluted with ethyl acetate to remove by-products, then the desired product was eluted with a mixture of ethyl acetate and methanol in volume. the ratio 1: 1. The fractions containing the title compound of the present example were combined and evaporated to dryness to give 1.5 g (43%) of a yellow gum, which crystallized on standing. melting point 115-117 ° c.

B. Alternatively, reflux dl-trans-2-benzyl-8-fluoro-5- (p-fluorophenyl) -2,3,4,4a, 5,9b-hexahydro-1H-pyrido [α, 3-b ] indole hydrochloride in the presence of an excess of. ethyl chloroformate or the corresponding methyl, isopropyl or n-butyl chloroformate, whereupon the compound given in the heading of the present example was obtained by hydrolysis and work-up in the manner indicated above.

Example 5: dl-trans-8-fluoro-5- (p-fluorophenyl) -2-methyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [α, 3-bindole hydrochloride.

A. 573 mg (2.0 mmol) of 8-fluoro-5- (p-fluorophenyl) -2,3,4,4a, 5,9b-hexahydro-1H were charged to a 25 ml flask equipped with a stirrer, dropping funnel and nitrogen inlet tube. -pyrido [,, 3-h] -indole, 8 ml of dichloromethane and 0.323 ml (4 mmol) of dry pyridine. To the solution thus obtained was added dropwise at room temperature a solution of 0.219 ml (2.3 mmol) of ethyl chloroformate. After the addition was complete, the mixture was stirred for one hour. The mixture was then evaporated in vacuo to give a rubber which was evaporated. This was partitioned between 10 ml of 10% hydrochloric acid and ml of ether. The organic phase was washed with water (10 ml), dried over magnesium sulphate and evaporated to dryness to give 707 mg of 8-fluoro-5- (p-fluorophenyl) -2-ethoxycarbonyl-2,3,4,4a. 5,9b-hexahydro-1H-pyrido-, [[3,3-h] indole, which was used in the following steps.

B. In a 100 ml flask equipped with a magnetic stirrer, dropping funnel and nitrogen inlet tube was charged 10 ml of ethyl ether and 524 mg (13.8 mmol) of lithium aluminum hydride. The suspension was cooled using an ice bath. After stirring under a nitrogen atmosphere for 5 minutes, a solution of 707 mg (1.97 mmol) of the product prepared as described above under A in 5 ml of ether was added dropwise over 5 minutes.

The mixture thus obtained was then stirred at room temperature for one hour, then 3 g of anhydrous sodium sulfate and then slowly about 1 ml of water were added. After stirring for 30 minutes, the resulting solution was filtered and the white solid collected on the filter was washed with ether. The filtrate was evaporated to dryness, the evaporation residue was dissolved in ether and a saturated solution of anhydrous HCl in ether was added until the precipitation was complete. The precipitate thus obtained was filtered off to give 481 mg of the title compound of the present example. IR spectrum (KBr), p: 2.92; 3.42; 3.02-4.10; 6.64; 6.80; 7.97; 8.23; 8.55; 8.73; 11.94; 12.35; 12.90. Mass spectrum, m / e 300, 256, 240, 242, 229, 201, low, 109, 95, 74, se (109%). 1 H NMR 2.50 (1H, m), 2.52 (3H, s), 2.98-3.26 (3H, m), 3.46-3.64 (1H, m), 6.50 7.46 (7 H, m).

Example 6: dl-trans-2- (4-hydroxy-4-phenylbutyl) -5-phenyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [α, 3-bindole hydrochloride .

A. To a suspension obtained by mixing 865 mg (4.20 mmol) of dicyclohexylcarbodiimide and 748 mg (4.20 mmol) of 3-benzoylpropionic acid in 30 ml of dichloromethane at 0 ° C was added 1.0 g (4.0 mmol) of dl-trans -5-phenyl-2,3,4,4a, 5,9b-448 459 _19 .. hexahydro-1H-pyrido [Ä, 3-b] indole in 10 ml of the same solvent. The mixture thus obtained was stirred and its temperature was allowed to rise to a value corresponding to room temperature over the course of two hours. After the reaction mixture was again cooled to 0 ° C, it was filtered, washed with dichloromethane and the filtrates were evaporated to give an evaporation residue consisting of dl-trans-2 - [(3-benzoyl) propionyl] -5-phenyl-2,3 , 4,4a, 5,9b-hexa-hydro-1H-pyridolβ, 3-h] indole, which was used without purification in the following steps.

B. The evaporation residue obtained under A above was dissolved in 50 ml of tetrahydrofuran and the solution was heated to reflux. A filtered solution of lithium aluminum hydride in the same solvent was added until gas evolution ceased (molar excess) and the resulting mixture was stirred under reflux for 5-10 minutes, then cooled. Anhydrous powdered sodium sulfate (17 g) and then 0.5 ml of water were added. The mixture thus obtained was stirred at room temperature for 30 minutes, filtered and the filtrate was evaporated to dryness in vacuo. The residue was chromatographed on a column containing 80 g of silica gel. Elution was performed with a 4: 1 mixture of ethyl acetate and methanol. Evaporation of the solvent gave the free base of the title compound of the present example. It was dissolved in ether and converted to the hydrochloride by the addition of a saturated solution of anhydrous HCl in ether, until the precipitate was complete. The precipitate was filtered off and dried, yielding 1.04 g with a melting point of 222-ZZAOC. IR spectrum (KBr), p: 2.97; 3.43; 4.00 (board); 6.25; 6.68; 6.88; 7.51; 7.96; 8.18; 8.45; 9.82. Mass spectrum m / e, 0398, 292, 263, 249, 220, 207, 192 (100%). UV (methanol) Å max 245 (5 = 0.653 x 104), 270 (ä = 0.914 x 104). Example 7: Using at least among the free bases prepared according to Examples 2 and 4 selected suitable starting material and suitable 3-benzoyl-propionic acid, the following dl-trans compounds were prepared in a manner as set forth in Example 6.

The products were isolated in the form of hydrochlorides unless otherwise stated. x »__.- * .m“ NCH cH cH cH "I fz 2 2. - <\ / rz \ \ \ N / l oH l Y Ä X Ä Melting point, OC Yield,% FFH 220-223 18 HHF 239- 245 39 HH CH 3 O amorphous, solid 54 substance (a) FF CH 3 O 45-48.5 (b) 31 (a) Mass spectrum, m / e: 428, 411, 263, (10%), 220, 206, 204: IR spectrum (Kßr), p: 2.98 3.42, 4.07 (broad), 6.20, 6.26, 6.70, 6.88 8.04, 8.54, 9.77, 12 (B) Melting point and yield apply to the free base Example 8: dl-trans-5-phenyl-2- [8- (p-fluorobenzoyl) propyl] -3,4,4a, 5,9b- 1H-pyrido [4,3-b] indole hydrochloride.

In a 25 ml reaction vessel equipped with a magnetic stirrer, a nitrogen atmosphere was maintained and 0.828 ml (8.0 mg, .3 mmol) of dry pyridine and 10 ml of dichloromethane were charged. To the solution was added 517 mg (5.17 mmol) of chromium trioxide, and the dark red suspension thus obtained was stirred for 15 minutes at room temperature. A solution of 359 mg (0.62 mmol) of dl-trans-5-phenyl-2- [α-hydroxy-4- (p-fluorophenyl) butyl] -2,3,4-aa, 5,9b-hexahydro- 1H-PyridoZh, 3-a71ndO1 (free base) 1 ml of dichloromethane was added in one portion. The reaction mixture changed rapidly to a brown suspension. This was stirred at room temperature for 30 minutes. The insoluble matter was filtered off, washed with dichloromethane and the filtrate combined with the washings was extracted with 20 ml of a 10% sodium hydroxide solution. The organic phase was dried (MgSO 4) and evaporated to dryness in vacuo to give a gum as evaporation residue. This was purified by column chromatography on silica gel, eluting with a 1: 1 mixture of hexane and ethyl acetate. The fractions containing the desired product were combined, evaporated to a yellow gum, taken up in ethyl ether and the solution treated with anhydrous HCl. The suspension thus obtained was evaporated to dryness, slurried in 3 ml of cold dichloromethane to give a colorless solid which was filtered off and dried, yielding 20 mg of the title compound of the present example, m.p. 244-246.5 ° C.

Example 9: dl-trans-8-fluoro-5- (p-fluorophenyl) -2- [3 (p-fluorobenzoyl) propyl] -2,3, A, 4a, s, ewb-hexahydro-1n-pyrido , s-bjindoi hydrochloride.

A 100 ml flask containing 20 ml of dichloromethane and 1.76 ml (21.9 mmol) of pyridine was charged with 1.09 g of chromium trioxide and the dark suspension thus obtained was stirred at room temperature for 15 minutes. Then 824 mg (1.82 mmol) of dl-trans-8-fluoro-5- (p-fluorophenyl) -2- [α-hydroxy-4- (p-fluorine) were added in one portion and dissolved in 10 ml of dichloromethane. phenyl) butyl] -2,3,4,4a, 5,9b-hexahydro-1H-pyrido [N, 3-bY-indole in the form of the free base (obtained from the hydrochloride by making an aqueous solution alkaline with sodium hydroxide, extracted with dichloromethane and the extract evaporated to dryness). The red-brown suspension thus obtained was stirred at room temperature for one hour and worked up in the manner used in Example 12 to give Z5 mg of the desired product, m.p. 260 DEG-63 DEG. e Ä X Å 4 H p-fluorine H Ä H m-fluorine o-fluorine 4 H o-fluorine p-methoxy 4 HH 0-methoxy 3 H p-fluorine p-fluorine 3 H o-fluorine o-fluorine 3 HF -fluoro p-fluoro 3 H m-fluoro p-fluorine Example 10: dl-trans-8-fluoro-5- (p-fluorophenyl) -Z- [α-hydroxy-4- (p-fluorophenyl) butyl] -2,3,4,4a, 5,9b-hexahydro-1H-pyridol β, 3-b] indole acetate. 1g dl-trans-8-fluoro-5- (p-fluorophenyl) -2- [α-hydroxy-4- (p-fluorophenyl) butyl] -2,3,4,4a, 5,9b-hexahydro-1H -pyrido [1,3-h] -indole hydrochloride in 75 ml of water was treated with 3 ml of water containing 1.0 g of sodium hydroxide and the liberated free base was extracted into 150 ml of diethyl ether. The ether phase was separated, dried over magnesium sulfate and treated with 1 ml of glacial acetic acid. The organic solvent and excess acetic acid were removed under reduced pressure and the residue was triturated with hexane and filtered.

Similarly, other acid addition salts, especially those with pharmaceutically acceptable acids, can be prepared.

Claims (2)

448 459 _25- PATENT REQUIREMENTS 4a, 9b-trans-hexahydro-γ-carboline compounds X Y-carboline compounds. A compound according to claim 1, characterized in that in formula (X) X is fluorine and Y is p-fluorine. 1983.10.27