HU188802B - Process for preparing trans-2-substituted-5-aryl-2,3,4, 4a,5,9b-hexahydro-1h-pyrido/4,3-b/indole derivatives - Google Patents

Abstract

The invention relates to a process for the preparation of a hexahydrocarboline compound of formula VI and the pharmaceutically acceptable salts thereof, wherein the hydrogen atoms bonded to the carbon atoms in the 4a and 5b positions are in a trans-arrangement with each other, X and Y are the same or are different and are hydrogen or fluorine, n is 3 or 4 and Z is hydrogen, fluorine or methoxy. These compounds are suitable as transquillizers. According to the invention, the free base of certain 4a, 9b-trans-hexahydro-carboline compounds is acylated with a selected carboxylic acid or an acid chloride or acid bromide thereof to obtain a 4a, 9b trans-hexahydro-carboline compound which reacts with lithium aluminum hydride in the presence an inert solvent is reduced. One possible final product is d & ind1! -Trans-2- (4-hydroxy-4-phenylbutyl) -5-phenyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido & 4,3-b! -Indole hydrochloride by the mentioned reduction of d & ind1! trans-2 - & (3-benzoyl) -propronyl)! - 5-phenyl-2, 3, 4, 4a, 5,9b-hexahydro-1H-pyrido & 3,3-b! indole is obtained.

Description

The present invention relates to novel trans-2-substituted-5-aryl-2,3,4,4a, 5,9b of formula VI.

- hexahydro-1H-pyrido [4,3-b] indole, which are useful as tranquilizers.

When reserpine and chloro-promazine were introduced as psychotherapeutic drugs in the early 1950s, great efforts have since been made to research other sedatives with better biological properties; many of these sedatives are gamma-carboline derivatives, also known as pyrido [4,3-b] indole derivatives.

In U.S. Patent No. 3,687,961, 8-fluoro-2- (3- (4-fluorophenylanilino) propyl) -1,2,3,4-tetrahydro

gamma - carboline is described as an effective sedative for warm - blooded people. U.S. Pat. No. 3,755,584 attributes similar activity to structurally related compounds containing the 6-or 8-position fluorine atom and the 2-position-substituted phenylalkyl group defined at the 2-position.

U.S. Patent 3,983,239 discloses hexahydro-gamma carbolines of formula I wherein R ^{1 is} methyl or ethyl and R ^{5 is} hydrogen or methyl or ethyl. No mention is made in this specification of the stereochemistry of the hydrogen atoms attached to the carbon atoms 4a and 9b. However, they are believed to be in the cis position by the method by which the hexahydro-gamma-carboline nucleus of the 1,2,3,4-tetrahydro-gamma-carboline precursor is prepared by catalytic hydrogenation in the presence of platinum; in fact, this method is a well-known procedure for introducing hydrogen atoms into the C = C double bond in cis -conjugation. The above compounds are agents for the treatment of psychoses used to treat schizophrenia.

U.S. Patent No. 3,991,199 discloses hexahydropyrimido [4,3b] indoles as analgesics and tranquilizers, some of which are important as hypnotics, some as muscle relaxants, and some as antihypertensive agents; these compounds and their pharmaceutically acceptable salts have the general formula (2) wherein the hydrogen atoms attached to the carbon atoms 4a and 9b are trans-relative to one another and when V is hydrogen

X ^is hydrogen, chlorine, bromine, methyl, tert-butyl or methoxy; and if

Y 'is trifluoromethyl, then Y'hydrogen; and

R "is hydrogen, 3-chloro-2-butenyl, 2-bromoallyl, benzoyl, benzyl in the ring substituted with methyl, methoxy or chloro, phenyl, 3-phenylpropyl, in the ring substituted with chloro, bromo or methoxy. 3-phenylpropyl, furfuryl, 2-thienyl, C 1-5 alkyl, C 3-5 alkenyl, C 3-5 alkynyl, cinnamyl, in the ring with chloro, bromo or methoxy; substituted cinnamyl, 3-phenyl-2-propynyl, C3-C7 cycloalkyl, C4-C8 cycloalkylmethyl, (methylcyclopropyl) methyl, (cis-2,3-dimethylcyclopropyl) methyl (C8-C8) cycloalkenylmethyl, C 6 -C 8 cycloalkadienylmethyl, (2,3-dimethylcycloprop-2-en-1-yl) methyl exo-7-norcarylmethyl, (cis

1,6-dimethyl-endo-3-norcaren-1-yl) methyl (4-methylbicyclo [2.2.2] oct-1-yl) methyl, (4-methylbicyclo [2.2.2] oct) - 2 - en I - yl) - methyl, (bicyclo [2.2.2] hept - 2 - yl) - methyl bicyclo [2.2.2] hept - 2 - en - 5 - yl) - methyl 1 - adamantyl - methyl or 2 - adamantyl

- represents a methyl group.

Recent Belgian Patent No. 845,368 (Derwcnt No. 00043Y) describes 5-phenylhexahydro-beta-carbolines which may be optionally methyl or ethyl at the 2- and 4-positions and C 1-3 alkyl at the 3-position. allyl or propargyl substituent. These compounds are useful as anti-depressant agents.

The recent German Patent Publication No. 2,631,836 (Derwent No. 09738Y) discloses structurally similar octahydropyrido [4 ', 3'; 2,3] indolo [1,7-ab] - [l (benzazepines) which can be represented by the above general formula 2, wherein

Y “ethylene bridge between the two benzene rings,

X ^is hydrogen and

R ^is -CH ₂ -CHjCHjCOCHj CHjCOO H ₅ group.

These compounds are useful as analgesic and sedative active ingredients.

U.S. Patent No. 4,001,263 discloses 5-aryl 1,2,3,4-tetrahydro-gamma-carboline damping agents of formula 3 wherein

X ^h and Z ^{b are} hydrogen or fluorine and R ^b includes, inter alia, the meaning of the substituent R given in formula (I).

188 802

Unexpectedly, it has now been found that the trans-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indoles of the present invention have a much more sedative effect than the corresponding 1,2,3,4-tetrahydro - gamma

carboline compounds.

Valuable active compounds of the present invention are compounds of formula VI and pharmaceutically acceptable salts thereof, wherein the hydrogen atoms attached to the carbon atoms of positions 4a and 9b are trans-relative to one another.

X and Y are the same or different and are hydrogen or fluorine, n = 3 or 4, and

Z represents hydrogen, fluorine or methoxy.

The disclosure also provides a method for treating schizophrenic disorders in a mammal, comprising administering to said mammal a sedative amount of a compound of Formula VI orally or parenterally, if necessary.

Also described herein are pharmaceutical compositions containing a compound of Formula VI as an active ingredient, together with pharmaceutically acceptable carriers.

The compounds of the present invention, as sedatives, significantly and unexpectedly outperform the above-mentioned suppressants.

Particularly preferred are enantiomers and racemic mixtures of the following compounds:

trans-8-Fluoro-5- (p-fluorophenyl) -2- [4-hydroxy-4- (p-fluorophenyl) butyl] -2,3,4,4a, 5,9b

- hexahydro - 1H - pyrido [4,3 - b] indole; trans-5-phenyl-2- [4-hydroxy-4- (p-methoxy 35

- (phenyl) -butyl] -2,3,4,4a, - 5,9b-hexahydro-1H-pifido [4,3- b] indole;

trans-8-Fluoro-5- (p-fluorophenyl) -2- [4-hydroxy-4- (p-methoxyphenyl) butyl] 2,3,4,4a, 5,9b-hexahydro-1H- pyrido [4,3 - b] indole; 40 trans-5-phenyl-2- (4-hydroxy-4-phenylbutyl)

- 2,3,4,4a, 5,9b - hexahydro - 1H - pyrido [4,3 - b] indole;

trans-8-Fluoro-5- (p-fluorophenyl) -2- (4-hydroxy-4-phenylbutyl) -2,3,4,4a, 5,9b-hexahydro

- 1H - pyrido [4,3 - b] indole;

trans-8-Fluoro-5- (o-fluorophenyl) -2- [4-hydroxy-4- [p-fluorophenyl] butyl] -2,3,4,4a, 5,9b

- hexahydro - 1H - pyrido [4,3 - b] indole;

trans-5-phenyl-2- [4-hydroxy-4- (p-fluoro- ^50- phenyl) -butyl] -2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole.

The free bases of Formula X serve as precursors of the new compounds of Formula VI ₅₅ , wherein X, Y and Z are as defined above.

AX Compound ₆₀ kai savbromidokkal or acylated with acids or the corresponding savkloridok- general formula XII, XIII képlelíi intermediate. When the acids of Formula XII are used for acylation, the acid and the compound of Formula X are reacted in an equimolar amount in the presence of an inert organic solvent and known condensing agents for forming peptide bonds. Examples of such materials are carbodiimides such as dicyclohexylcarbodiimide and 5-ethyl-3- (3-dimethylaminopropyl) carbodiimide and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide. hydrochloride; and alkoxyacetylenes such as methoxyacetylene and ethoxyacetylene. A preferred condensing agent is dicyclohexylcarbodiimide. Examples of the solvent include dichloromethane, chloroform, tetrahydrofuran, ethyl ether and benzene. Although the reaction is satisfactory, temperatures of from about -10 ° C to about 50 ° C, preferably from about 0 ° C to about 30 ° C, are used. At this temperature range, the reaction is complete at ¹⁵ feet in a few hours. For example, to isolate the product of formula XIII, the insoluble material is removed by filtration and the solvent is evaporated. The resulting product is usually pure enough for further processing has ²⁰ Ref.

The intermediate of Formula ΧΠ1 is then reacted with lithium aluminum hydride in the manner described in Hungarian Patent No. 185,009, to prepare the 2-methyl compounds of Formula XI. The product of formula VI is isolated and purified, for example, by silica gel column chromatography.

The free bases of the formula X, which are described in two Hungarian Patent Specifications No. 185,009, are prepared as follows.

Reduction of the tetrahydro-gamma carbolines of Formula VIII to 4a, 9b-trans hexahydro compounds of Formula IX, wherein X and Y are the groups represented by Formula VI and can be cleaved by R ₂ reduction in an ethereal solvent. is usually carried out in tetrahydrofuran. In order to achieve complete reduction, the borane / THF complex (BH ₃ .THF) is generally used in a molar excess, with a molar excess of 100 to 2 µU being preferred. Although the reaction is carried out at -10 ° C to 80 ° C, it is preferable to use 0-65 ° C. Generally, a solution of the Vili starting material in tetrahydrofuran is added to an ice-cold BH ₃ .THF solution and the reaction mixture is heated to reflux and maintained at this temperature for 1-2 hours or more. The reaction is usually carried out in the presence of an inert gas such as N ₂ . After completion of the reaction, the solvent is evaporated and the residue is acidified with excess acid, such as 2 to 12 molar hydrochloric acid, preferably 1: 1 acetic acid / 5 molar hydrochloric acid. The acidified mixture is generally heated to reflux for 1-2 hours or more. The desired product is then isolated, for example, by evaporation of the remaining ethereal solvent and a portion of the acidic mixture, and the precipitated product is collected by filtration and washed. Otherwise isolation of the product of Formula IX, after refluxing, the reaction mixture is filtered, the filtrate is cooled and made basic, for example, sodium hydroxide. potassium hydroxide or sodium carbonate. Alkaline light cores with a water-immiscible organic solvent,

For example, the extracts are evaporated and the residue is purified by silica gel column chromatography, for example, eluting with ethyl acetate or hexane / ethyl acetate. 5

The tetrahydro-gamma carbolines are reduced with the BH ₃ -THF complex and then treated with acid to give hexahydro-gamma carbolines where the hydrogen atoms attached to the 4a and 9b carbon atoms are trans-relative to one another (see, e.g., U.S. Pat. No. 3,991,199). United States Patent).

The 2-benzyl compounds of formula IX are then converted to the corresponding 2-hydrogen compounds of formula X, generally by reacting a compound of formula IX ¹⁵ with a lower alkyl chloroformate ester such as methyl, ethyl, propyl or with a molar excess of isobutyl ester in the presence of a suitable solvent inert to the reaction followed by alkaline hydrolysis. Paper of worm ²⁰ due to the availability and efficacy of the preferred basis of the chloroformate ester is ethyl chloroformate.

For the reaction under an inert suitable solvent defines a solvent which dissolves the reactants under the reaction circumstances _{2 &} forms, without the formation of byproducts. Such solvents include certain aromatic hydrocarbons, such as benzene, toluene and xylene, chlorinated hydrocarbons such as chloroform and 1,2-dichloro-ethane, diethylene glycol dimethyl ether, and di-methyl sulfoxide _3Q. A particularly preferred solvent is toluene.

To a mixture of the starting material of formula IX and the above inert solvent is added up to about 10 molar excess of chloroformate ester. For reasons of economy, 3-5 molar excesses are preferred. The resulting mixture is then heated to about 80-150 ° C, typically at the reflux temperature of the mixture, for about 6-24 hours or more. Usually, the reflux is performed overnight for convenience. The reaction mixture is then evaporated in vacuo and the residue taken up in the alcohol / water mixture is treated with an alkali, e.g. overnight. The solvent is evaporated and the residue is shaken with water and a water immiscible solvent such as chloroform, methylene chloride or ethyl ether and the organic phase is evaporated to dryness. , e.g., after purification by column chromatography. ⁵¹⁵

As mentioned above, the basic compounds of the present invention may form acid addition salts. To prepare these acid addition salts, the base is reacted with an acid in an aqueous or non-aqueous medium. Similarly, the acid addition salts are reacted again with the free base form by treatment with an equivalent amount of aqueous alkali, such as alkali metal hydrochlorides, alkali metal carbonates and alkali metal bicarbonates, or an equivalent amount of metal cation which forms an insoluble precipitate with the acid anion. The bases thus regenerated can be converted into the same or different acid addition salts.

When the salts of the compounds of the present invention are used for chemotherapeutic purposes, of course, pharmaceutically acceptable salts are preferred. Although water insolubility, high toxicity, lack of crystalline nature renders some salts unsuitable or unfavorable for pharmaceutical use, the water insoluble or toxic salts can be converted into the corresponding pharmaceutically acceptable bases by any desired method of decomposition or can be converted into pharmaceutically acceptable acid addition salts.

Pharmaceutically acceptable anionic acids include hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, sulfuric, phosphoric, acetic, lactic, citric, tartaric, succinic, maleic or gluconic acid.

As mentioned above, the compounds of the present invention may be used as a sedative in mammals.

The sedatives containing the active ingredient of the present invention are useful in alleviating the symptoms of schizophrenia in humans, such as hallucinations, hostility, suspicion, emotional or social withdrawal, anxiety, restlessness and tension. An amphetamine-induced symptom inhibition assay in a standard rat, which is excellent for comparing the sedation effect of this class of compounds with human efficacy (A. Weissman et al., J. Pharmacol. Exp. Ther. 131, 229 [1966] and Quinton et al.) , Naturre 200, 178 [1963]).

The gamma-carbolurets useful as receipts can be used as their pharmaceutically acceptable salts, alone or in combination with other drugs. They may be used alone, but will generally be administered together with a pharmaceutical carrier selected according to the mode of administration and general pharmaceutical practice. For example, they may be administered orally in the form of tablets or capsules containing excipients such as starch, milk sugar, certain substances, and the like. They may also be used in the form of elixirs or oral suspensions, wherein the active compounds are combined with emulsifying and / or suspending agents. They can also be injected parenterally, whereby the active compounds or suitable derivatives thereof are processed into sterile aqueous solutions. These aqueous solutions are buffered if necessary and rendered isotonic with other substances such as salt or glucose.

Although the compositions containing the compounds in question are generally useful in the treatment of mammals, they are intended primarily for human treatment. Ultimately, the most appropriate dosage for the individual is determined by the attending physician. considering the patient's age, weight, and individual response.

188,802 and the pharmacodynamic characteristics of the compound used. Generally, small doses are initially administered, which are gradually increased until the optimum level is reached. It is often observed that oral administration of the composition requires higher amounts of the active ingredient to achieve the same effect as parenteral administration.

In view of the above factors, it is believed that the compounds of the present invention provide a suitable sedative effect in humans at a daily dose of about 0.5 mg to about 100 mg, particularly about 1 mg to about 25 mg. For individuals with prolonged action of the compounds in question, 5 to 125 mg per week may be administered in one or two divided doses.

The above values are indicative and may, of course, be individual cases where lower or higher dosage ranges are required.

Each compound of Formula VI has at least ²⁰ asymmetric centers due to the reduction of the 4a, 9b double bond to a system containing a trans configuration. The invention encompasses racemates as well as the individual enantiomers. In addition, when the 2-position substitutions ^_5 substituent (R) contains a group which can be present in stereoisomeric forms, all possible diastereomers are included within the scope of the invention.

The following examples illustrate the invention _3θ without restricting the invention since many modifications and variations therein without departing from the spirit and scope of the invention.

- butyl] -2,3,4,4a, 5,9b - hexahydro - 1H - pyrido [4,3

bjindole is dissolved in 40 ml of toluene and added

5.3 ml (55.7 mmol) of ethyl chloroformate. The mixture is refluxed overnight and evaporated to dryness to give a gum. To this was added 200 mL of 9; 1: v / v ethanol / water. After the gum was dissolved, 15 g of potassium hydroxide was added and the mixture was refluxed overnight. The solvent was evaporated in vacuo and the residue was shaken with water and chloroform. The organic extracts were washed with water, dried over sodium sulfate and evaporated to dryness. The residual oil was taken up in ethyl acetate and passed through a silica gel column; eluting with ethyl acetate to remove by-products, then eluting the desired product with ethyl acetate / methanol (1: 1). The fractions containing the title compound were combined and evaporated to dryness to give 1.5 g (43 g of a yellow gum) which crystallized on standing, m.p. 115-117 ° C.

B. Alternatively, dl - trans - 8 - fluoro

- 5 - (p-Fluorophenyl) -2,3,4,4a, 5,9b - hexahydro 1H-pyrido [4,3-b] indole hydrochloride in excess of elyl chloroformate or the corresponding methyl, isopropyl or in the presence of an ester of n - butyl chloroformate under reflux, then hydrolyzed and worked up according to the procedure described above to give the title compound.

Example 1 dl-trans-5-Phenyl-2,3,4,4a, 5,9b-hexahydro 1H-pyrido [4,3-b] indole

4.17 g of dl-trans-2-benzyl-5-phenyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole hydrochloride suspended in 150 ml of absolute ethanol 3.5 kg / ^cm2 pressure, Pd / C catalyst was hydrogenated at 60-70 ° C, 1.0 g of 10% for 2 hours. The catalyst was removed by filtration and ethyl ether was added to the filtrate to precipitate the hydrochloride of the desired product.

Yield: 2.76 g (87%); mp 235-237 ° C.

The hydrochloride salt is converted to the free base by shaking with ether and dilute sodium hydroxide solution. The ether layer was dried over sodium sulfate and evaporated to give the title compound (97%); mp 74-76 ° C. 55

Example 2 dl-trans-8-Fluoro-5- (p-fluorophen) 2,3,4,4a, J, 9b-hexahydro-1H-pyrido [4,3-b] indole

A. 5.6 g (12.4 mol) of dl-trans-8-fluoro-5- (p-fluorophenyl) -2- [4-hydroxy-4- [p-fluorophenyl] dl-trans- 2- (4-Hydroxy-4-phenyl-hoolyl) -5-phenyl! - 2,3,4,4 a, 5,9b - hexahydro - 1H - pyrido [4,3 bjindole hydrochloride

A. To a suspension of 865 mg (4.20 mmol) of dicyclohexylcarbodiimide, 748 mg (4.20 mmol) of 3-benzoylpropionic acid and 30 mL of dichloromethane at 0 ° C, 1.0 g (4.0 mmol) ) dl-trans-5-phenyl-2,3,4,4a, 5,9b

- hexahydro-1H-pyrido [4,3-b] indole dissolved in 10 ml dichloromethane. The mixture was stirred and allowed to warm to room temperature over 2 hours. The reaction mixture was again cooled to 0 ° C, filtered, washed with dichloromethane and the filtrates evaporated to give dl-trans-2 - [(3-benzoyl) propionyl] -5.

- phenyl - 2,3,4,4a.5,9b - hexahydro - 1H - pyrido [4,3

- bjindole is obtained which is used without further purification in the following step.

H. The above product is dissolved in 50 ml of tetrahydrofuran and heated to reflux. Filtered lithium aluminum hydride, soluble in telrahydrofurans

- dd until gas evolution ceases (molar excess) and the mixture is stirred at reflux for 5-10 minutes and then cooled. 17 g of powdered anhydrous sodium sulfate are added followed by 0.5 ml of water. The mixture was stirred at room temperature for 30 minutes, filtered and the filtrate evaporated to dryness in vacuo. The residue was chromatographed on a column containing 80 g of silica gel. eluent, 188 8 (4: 1 ethyl acetate: methanol). After evaporation of the solvent, the free base of the title compound is obtained. The free base is converted to the hydrochloride salt by adding a solution of saturated ethereal hydrogen chloride in ether. The precipitate was filtered off and dried, yielding 1.04 g of product, m.p. 222-224 ° C.

Infrared (KBr), μ: 2.97; 3.43; 4.00 (broad); 6.25; 6.68; 6.88; 7.55; 10.96; 8.18; 8.45; 9.82.

Mass Spectrum, m / e: 398, 292, 263, 249, 220.207,

192 (100%).

Ultraviolet Absorption Spectrum (methanol), γ, _υιν 245 (ε = 0,653.10 ^4). 270 ¹⁵ (ε = 0.914.10 ⁴ ).

Example 4

Using the appropriate starting material selected from the free bases prepared in Examples 1 and 2 and the appropriate 3-benzoylpropionic acid, the following d1-trans compounds of formula XVI were prepared according to the procedure of Example 4. The products are isolated as their hydrochloride salts unless otherwise indicated.

Compound of Formula XVI

Who-

X Y Z Melting point, ° C production, y / 0 F F H 220-223 18 H H F 239-245 39 H H CHjO amorphous solid (a) 54 4c, F F CHjO 45-48.5 (b) 31

1 _'2 (a) Mass spectrum, m / e: 428, 411, 263 (100%),

220, 206, 204.

Infrared (KBr), μ: 2.98; 3.42; 4.07; (wide); 6.20; 6.26; 6.70;

6.88; 8.04; 8.54; 9.77; 12.05.

(b) Melting points and yield data refer to the free base.

Example 5

Test methods and results

The effects of the compounds of the present invention on amphetamine-induced pathological symptoms in rats are investigated using the assay method described by Quinton and Halliwell and Weissman. Groups of 5 to 5 rats were placed in covered plastic cages of approximately 26 x 42 x 16 cm. After a short acclimatization to the cage, each group of animals is treated subcutaneously (s.c.) with the test compound. After 1, 2 and 24 hours, the animals are treated intraperitoneally (i.p.) with 5 mg / kg of d -amphetamine sulfate. One hour after the administration of amphetamine, the animals were observed to make circular motions for amphetamine activity in the cages. The dose / effect curve following amphetamine treatment can be used to determine the effective dose of test compound that inhibits amphetamine-specific cage behavior in 50% of the animals (ED 4). The selected study duration coincides with the maximum amphetamine bite occurring 60-80 minutes after drug treatment.

Using the method described above, the following 4a, 9b-trans compounds of Formula 1 were tested for their ability to block animal behavior attributable to amphetamine effects. Results are reported as ED ₅₀ 5 mg / kg at the indicated times:

188 802

RD _W (mg per kg) hour 5 hours 24 hours

H H C ₆ H ₅ CH- (CH ₂ ) ₃ - 0.032 to 0.1 0.032 to 0.1 0.1 to 0.32 H OH p-FO _e H ₄ CH- (CH ₂ ) ₃ - 0.1 to 0.32 0.1 to 0.32 0.1 to 0.32 H H OH p -CH ₃ OC ₆ H ₄ CH- (CH ₂ ) ₃ - 0.1 to 0.32 0.1 to 0.32 ~ 1.0 F p-fluorophenyl OH C _e H _s CH- (CH ₂ ) ₃ - 0.1 to 0.32 0.1 to 0.32 <0.32 F p-fluorophenyl OH p-FO ₆ H ₄ CH- (CH ₂ ) ₃ - 0.32 0.32 <0.32 F p-fluorophenyl Oh p-fc ₆ h ₄ ch- (ch ₂ ) ₃ - 0.032 to 0.1 0.032 to 0.1 0.032 to 0.1 OH 8-Fluoro-5- (p-fluorophenyl) -2- [4-hydroxy-4- (p-fluorophenyl) butyl] -1,2,3,4, -tetrahydro-gamma-carboline ⁰¹ Navan ^(f) , after 0.1 to 0.32 0.32 to 1/0 0.1 to 0.32 > 10 0.32 to 1.0 > 32

Footnote ^(a) The corresponding 4a, 9b-cis analogue has an ED _M value of ~ 56 mg / kg at 1 hour.

United States Patent 4,001,263.

^, cis-9- [3- (4-Methyl-1-piperazinyl) propylidene] -2- (dimethylsulfonamido) lyxanthene, U.S. Patent No. 3,310,553.

Example 6 Pills

A tablet stock is prepared by blending the following ingredients in the ratios given below:

Sucrose 80.3

Tapioca starch 13.2

Magnesium stearate 6.5

The amount of trans-8-fluoro-5- (p-fluorophenyl) -2- [4- (p-fluorophenyl) -4-hydroxybutyl] -2,3,4,4a, 5 9b-hexahydro-1H-pyrido [4,3-b] indole hydrochloride, 1.0; 2.5; Tablets containing 5.0 and 10 mg of active ingredient are obtained. The mixture is compressed into tablets weighing 360 mg by conventional means.

Example 7 Capsules

We make a mixture of the following components:

Calcium carbonate 17.6 Dicalcium phosphate 18.8 Magnesium trisilicate 5.2 Lactose 5.2 potato starch 5.2 Magnesium stearate 0.8

To mixture F was added additional magnesium stearate (0.35 g) and so much trans-5-phenyl-2- (4-hydroxy-4-phenylbutyl) -2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4 , 3 - bindindole hydrochloride to give 1.0; Capsules containing 2.5, 5.0 and 10 mg of active ingredient are obtained. The mixture is filled into standard hard gelatin capsules at 350 mg per capsule.

188 802

Example 8 Suspension of trans-8-Fluoro-5- (p-fluorophenyl) -2- [4

- hydroxy-4- (p-methoxyphenyl) butyl] 2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole

- a suspension of acetate having the following composition:

Active ingredient 25.00 g% aqueous sorbitol 741.29 g

Glycerin 185.35 g

Arabic Gum (10% solution) 100.00 ml

Polyvinylpyrrolidone 0.50 g

Distilled water up to 1 liter

Various sweeteners and flavoring agents are added to this suspension to improve the taste of the suspension. The suspension contains about 25 mg of active ingredient per ml.

Example 9

Sesame oil is sterilized by heating for 2 hours at 120 ° C. To this oil, as much of the powdered trans-8-fluoro- (p-fluorophenyl) -2- [4- (p-fluorophenyl) -4-hydroxybutyl] -2,3,4,4a, 5,9b hexahydro-1H-pyrido [4,3-b] indole hydrochloride was added to give a suspension of 0.025% by weight.

The solid is dispersed in the oil by means of a colloidal mill, filtered through a 100-25 mesh sieve, filled into sterile vials and sealed.

Claims (6)

Claims A process for preparing hexahydrogammacarboline compounds of formula VI wherein: a The hydrogen atoms attached to the 4a and 9b carbon atoms are in trans position relative to one another, X and Y are the same or different and are hydrogen or fluorine, 5 n = 3 or 4 and Z is hydrogen, fluoro or methoxy and pharmaceutically acceptable salts thereof, characterized in that a 4a, 9b-trans-hexahydro-gamma carboline free base of formula X wherein X and Y are as defined above is substituted with a carboxylic acid of formula XII wherein Z and n are as defined above - or acylated with the corresponding acid chloride or sabbromiddal and ¹⁵ resulting XIII formula 4a, 9b - trans hexahydro - gamma - carboline - compound - wherein X, Y, Z and n are as defined above - the reaction is reduced in the presence of a substantially inert solvent with lithium aluminum hydride. ²⁰ 2. The process according to claim 1, wherein the reduction solvent is ethyl ether or tetrahydrofuran. 3. A method according to claim 1 and 2 taken ^ö EMBODIMENTS, characterized in that the reduction is carried out at room temperature. 4. The process of claim 1, wherein the acylation step is carried out in the presence of an inert organic solvent and a condensing agent. 5. The process of claim 4, wherein the condensing agent is 35 dicyclohexylcarbodiimide was used. The process according to any one of claims 1 to 5, wherein the acylation is carried out at a temperature of 0 ° C to 30 ° C.