DE2822465A1 - TRANS-2-SUBSTITUTED-5-ARYL-2,3,4,4A, 5,9B-HEXAHYDRO-1H-PYRIDO ANGLE CLAMP ON 4.3-B ANGLE CLAMP TO -INDOLDER DERIVATIVES AND THESE MEDICINAL PRODUCTS - Google Patents

Description

Trans- 2 -substituted-5-aryl-2,3,4-, 4-a, 5,9b-hexahydro-1H-pyridoiA, 3-bJ-indole derivatives and medicaments containing them

The invention "relates to certain trans-2-substituted-5-aryl-2,3 , ^, ^ a ^^ b-hexahydro-IH-pyrido [4,3-b] indole derivatives and their use as tranquilizers in medicaments containing them.

Following the introduction of reserpine and chlorpromazine in psychotherapeutic medicine in the early In the 1950s, great efforts were made in the search for other tranquilizers or tranquillants with improved, biological profiles undertaken, several of them are ^ -Carboline derivatives, also known in the art as derivatives of pyrido [4,3-b] indole are known.

In US Pat. No. 3,687,961, 8-fluoro-2- ί 3- (4-fluoro rphenylanilino) -propyl-1,2,3,4-tetrahydro-T-carboline was described as a useful tranquilizer for warm-blooded animals. In US Pat. No. 3,755,584, structurally related compounds having fluorine in the 6- or 8-positions and a specific, p-substituted phenylalkyl moiety in the 2-position are described as having similar activity.

U.S. Patent 3,983,239 describes hexahydro-7'-carbolines of the following formula:

8098Α8 / 09Θ0

Λ · ■ 2

where R is a methyl or ethyl radical and ß is a hydrogen atom, a methyl or ethyl radical. The stereochemical arrangement of the hydrogen atoms which are bonded to the carbon atoms in the 4a and 9b positions is not mentioned in this publication. However, they are believed to be in a cis arrangement due to the method of forming the hexahydro- ^ ¹ carboline ring from a 1,2,3 * 4-tetrahydro- ^ - carboline precursor compound by catalytic hydrogenation in the presence of platinum, a method well known in the art for introducing hydrogen atoms in a cis configuration into a carbon-carbon double bond. The indicated compounds are neuroleptic agents that are said to be useful in the treatment of schizophrenia.

In U.S. Patent 3,991,199 there are hexahydropyrimido- [4,3-bJ-indoles described, useful as analgesics and Sedati va, some of which are as tranquilizers, some as Muscle relaxants of interest and many of these compounds exhibit hypotensive activity; the described Compounds have the following formula:

and their pharmaceutically suitable salts, those bonded to the carbon atoms in the 4a and 9b divisions Hydrogen atoms are in a trans arrangement to one another,

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and wherein when Y ^a = -H, X ^a = -H, -Cl, -Br, -CH ₅ , -tert.-C ^ or -OCH, and when Y ^a = -Ci ¹ , X is ^a = -H and ß ^{a has} the meaning: hydrogen, 3-chloro-2-butenyl, 2-bromoallyl, benzyl, benzyl substituted on the ring by methyl, methoxy or chlorine; Phenethyl, 3-phenylpropyl; 3-phenylpropyl substituted at the input by chlorine, bromine or methoxy; Furfuryl; 2-thenyl; Cj-C 1 alkyl; C 1 -C 4 alkenyl; C 1 -C 4 alkynyl; Cinnamyl; cinnamyl substituted with chlorine, bromine or methoxy at the input; 3-phenyl-2-propynyl; C 1-12 cycloalkyl; C1 -C6 cycloalkylmethyl; (Methylcyclopropyl) methyl; (cis-2,3-dimethylcyclopropyl) methyl; Cg-Co cycloalkenylmethyl; Cg-C 1 -Cyoloalkadlenylmethyl; (2,3-dimethylcycloprop-2-en-i-yl) methyl; exo-7-horcarylmethyl; (cis-1,6-dimethylendo-3-norcaren-7-yl) methyl; (4-methylbicyclo2.2.2j oct-1-yl) methyl; (4-methylbicyclo L2.2.2] oct-2-en-1-yl) methyl; (BicycloC2.2.2] hept-2-yl) methyl; (Bicyclo [2.2.2] hept-2-en-5-yl) methyl; 1-adamantylmethyl or 2-adamantylmethyl.

In the recently published Belgian patent 845 368 (Derwent ITr. 00043Y) there are 5-phenyl-hexahydroß-carbolines described, which optionally in the 2- and 4-positions by methyl or ethyl and in the 3-position are substituted by alkyl having 1 to 3 carbon atoms, allyl or propargyl. These compounds are used as antidepressants useful.

In the recently published German Offenlegungsschrift 2,631,836 (Derwent No. 09738Y), structurally related octahydropyrido [4 ^l , 3 ': 2,3] -indolo [1,7-ab] [1] -benzazepine are described which are described by can be derived from the formula given above, in which Y ^{a is} an ethylene bridge between the two benzene rings, X ^{a is} a hydrogen atom and E ^{a is} an Eest -CH ₀ CH ₀ COCH, or -CH ₀ CH ₀ COC-Ht-.

₂ CH ₂ COCH,

These compounds are also stated to be useful as analgesics and as tranquilizers.

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In U.S. Patent 4,001,263 there are 5-aryl-1,2,3,4-tetrahydro-T'-carboline tranquilizers described by the following formula:

wherein X and Z are hydrogen or fluorine can, and the meanings of R can have the meaning as given above for E in the formula (I).

Surprisingly, it has now been found that the trans-2,3,4,4a, 5, ^ - hexahydro-IH-pyridoC 4,3-b] indoles according to the invention have markedly superior tranquilizer activity compared to the corresponding 1,2,3,4-tetrahydro-T-carbolines.

The compounds according to the invention which are useful as tranquilizers are the enantiomers and racemic compounds of the following formula:

N- (CII ₂ ) _η -Μ

(II)

as well as the pharmaceutically acceptable salts thereof, wherein those attached to the carbon atoms in the 4a and 9b positions bonded hydrogen atoms are present in a trans arrangement to one another and in which X ^ and Y, -, which are the same or different can be a hydrogen atom or fluorine atom,

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or is 4,

Il I

M is one of the groups -0- or -CH-, lind

represents a hydrogen atom, a fluorine atom or a methoxy group.

Further valuable tranquilizers according to the invention are the enantiomers and racemic compounds of the following Formula:

^{2 m}

(III)

as well as the pharmaceutically acceptable salts thereof, wherein the hydrogen atoms in the 4a and 9b positions in the same trans arrangement as before, X ^ and X ^ die have the meanings given above, m is the number 2 or 3 and Zq denotes a fluorine atom or a methoxy radical.

Further valuable tranquilizers according to the invention are the enantiomers and racemic compounds of the following Formula:

- (IV)

as well as the pharmaceutically acceptable salts thereof wherein the hydrogen atoms are in the 4a and 9b positions in the the same trans arrangement as indicated above are present, and

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where Xp and X ^, which can be the same or different, are each a hydrogen atom or a fluorine atom with Provided that if one of the radicals Xp and Yp is a hydrogen atom the other is a fluorine atom.

The invention further relates to methods of treating schizophrenic manifestations in mammals, wherein this method, the oral or parenteral application of a tranquilizing amount of a compound of the formulas II, III or IV in a mammal in need of such treatment.

The invention also relates to pharmaceutical compositions or drugs which are active as tranquilizers and a compound of the formulas II, III or IV, if appropriate together with a pharmaceutically acceptable carrier and / or diluent.

The compounds according to the invention have a pronounced and surprisingly high tranquilizer effect compared to the tranquilizers of the prior art already mentioned above.

Particularly preferred tranquilizers according to the invention are the enantiomers and racemic mixtures of: trans-8-fluoro-5- (p-fluorophenyl) -2-methyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido- [4, 3-b j -indole,

trans-8-fluoro-5- (p-fluorophenyl) -2- i 4-hydroxy-4- (p-fluorophenyl) -butyl 1-2,3,4, 4a, 5, 9b-hexahydro-1H-pyrido u 4, 3-b j -indole, trans -5-phenyl-2- L 4-hydroxy-4- (p-methoxyphenyl) -butyl j -2,3,4-4a, 5 * 9b-hexahydro-1H-pyrido [4,3-b -indole, trans-8-fluoro-5- (p-fluorophenyl) -2- _L -4-hydroxy-4- (p-methoxyphenyl) butyl 3-2,3,4,4a, 5, 9b-hexahydro-1 H-pyrido τ 4,3-b] -indo 1, trans-5-phenyl-2- (4-hydroxy-4-phenylbutyl) -2,3,4, 4a, 5, 9bhexahydro-1H-pyrido [4,3-b '_ -indole,

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trans-8-fluorine-5- (p-iluo3? plieiiyl) -2- (4-hydroxy-4-plieiiylbutyl) -

2,3,4,4a _i 5,9b-hexahydro-1H-pyridoL4,3-b] indole,

trans- ^ phenyl-2- [3- (p-fluorobenzoyl) propyl] -2,3,4,4a, 5,9b-

hexahydro-1H-pyrido L4,3-b j -indole,

trans-e-fluoro- ^ (p-fluorophenyl) -2- C 3- (p-fluorobenz oyl) -propyl] -

2,3,4,4a, 5, 9 *> - hexahydro-1H-pyrido C4,3-b] -indole,

trans-8-fluoro-5- (pf luophenyl) -2- [4- (pf luophenyl) -J-but enyl j -

2,3,4, 4a, 5.9 "b-kexabydro-1H-pyrido [4,3-b] -indole,

t r ans-8-I "luoro-5- (p-fluorophilic) -2- [4- (p-methoxypkenyl) -3-but enyl] -2,3,4, 4a, 5, 9t> -hexahydro-1 H-pyrido C 4,3-b] -indo 1, trans-8-fluoro-5- (of luorph.eiiyl) -2- C4-hydroxy-4- (pf luorplienyl) butyl] -2,3,4,4a, 5,9b-laexahydro-1H-pyridoC4,3- 'b] -indole, trans-5-plienyl-2- [4-hydroxy-4- (p-fluorophenyl) butyl] -2,3,4, 4a-

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

trans-8-i ^l luor-5- (of luorphenyl) -2- [4- (pf luorphenyl) -3-but enyl] -2,3,4, 4a, 5, 9b-hexahydro-1H-pyrido C 4 , 3 ~ b] -indole.

The following reaction scheme illustrates the procedures which are used for the synthesis of the 4a, 9b-trans-2-methyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] -indoles of the formula I, wherein E is the methyl radical and X and Y have the definition given above or the meaning of X _x and Yy. can be used:

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1 (VIII)

(2) II

9b

NO,

Y (IX)

(IX)

(2) KOH,

Λ *.

N-CH,

Y (XI)

(X)

(1) ClCO ₂ C ₂ H ₅

(2) LiAlH.

809848/0 9 60

A preferred meaning for Eo is benzyl from economic Establish. However, Ro can also have other meanings have, and these can also be used in the scheme given above, as the person skilled in the art per se known. Examples of such alternative meanings for Rp are substituted benzyl radicals on the benzene ring, e.g. B. as substituents of one or more in the form of methyl, methoxy, Nitro or phenyl radicals, as well as the benzhydryl radical.

The reduction of the tetrahydro- ^ carbolines of the formula VIII to form the 4a, 9b-trans-hexahydro compounds of the formula IX is carried out in an ether solvent, usually tetrahydrofuran. To ensure complete reduction, a molar excess of borane / tetrahydrofuran complex (BH-THF) is usually employed, and a 100% to 200% molar excess of this complex is preferred. Although the reaction can be carried out at a temperature in the range of about -10 ⁰ C to 80 ⁰ C, a temperature of about O ⁰ C to 65 C preferably. Usually a solution of the starting material of Formula VIII in tetrahydrofuran is added to an ice-cold solution of BH ^ .THF. After the addition is complete, the reaction mixture is heated to reflux and held at that temperature for a period of about 1 to 2 hours or more. The reaction is usually carried out in the presence of an inert gas such as nitrogen. When the reaction is virtually complete, the solvent is evaporated and the residue is acidified with an excess of acid such as 2 to 12M hydrochloric acid. A preferred acidifying agent is a mixture of equal volumes of acetic acid and 5M hydrochloric acid. The acidified mixture is refluxed usually for 1 to 2 hours or more. The desired product can then be isolated, for example by evaporating any remaining ethereal solvent and part of the acid mixture,

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and the precipitated product can be collected by filtration and washed. In an alternative method of isolating the product IX, the reaction mixture is after filtered by refluxing, the filtrate is cooled and by adding, for example, sodium hydroxide, potassium hydroxide or made alkaline sodium carbonate. The basic mixture is mixed with a water-immiscible, organic Solvents such as B. chloroform, methylene chloride or benzene extracted, the extracts are evaporated, and the residue is purified by column chromatography over silica gel, eluting e.g. B. by means of ethyl acetate or Mixtures of hexane / ethyl acetate, purified.

The reduction of the tetrahydro-T'-carbolines by BH ₅ .THF with subsequent acid treatment gives hexahydro -? ** - carbolines, in which the hydrogen atoms bonded to the carbon atoms in the 4 a and 9 b positions are in the trans arrangement available, see for example US Pat. No. 3,991,199

The 2-benzy! Compounds of the formula IX are then converted into the corresponding 2-hydrogen compounds of the formula X converted. In general, this can be done by treating the Compound of formula IX with a molar excess of a lower alkyl chloroformate such as methyl, Ethyl, propyl or isobutyl ester in the presence of one suitable, reaction-inert, organic solvent with subsequent alkaline hydrolysis can be carried out. Ethyl chloroformate is preferred as the chloroformate ester because of its easy accessibility and effectiveness. Under a suitable, reaction-inert, organic solvent is to be understood as a solvent that the reactants under the reaction conditions without the formation of By-products essentially dissolves. Examples of such

809848/0960

Solvents are aromatic hydrocarbons such as benzene, Toluene and xylene, chlorinated hydrocarbons such as chloroform and 1,2-dichloroethane, diethylene glycol dimethyl ether and Dimethyl sulfoxide. A particularly preferred solvent is toluene.

Up to about a 10-fold molar excess of the chloroformate ester is added to the mixture of the starting material of the formula IX in this reaction-inert, organic solvent. For economic reasons, a molar excess of about 3 to 5 times is preferred. The resulting mixture is then heated to a temperature of about 80 ⁰ C to 150 ⁰ C, typically up to the reflux temperature of the mixture, namely for periods of about 6 to 24 hours or longer. Usually, the reflux is done overnight for the sake of simplicity. The reaction mixture is then evaporated in vacuo and the residue is taken up in a mixture of alcohol-water. An alkali compound, e.g. B. sodium hydroxide or potassium hydroxide, in about 10-fold to JO-fold molar excess, based on the amount of the starting material of the formula IX, is added, and the resulting mixture is usually refluxed overnight. The solvent is then evaporated and the residue is partitioned between water and a water-immiscible organic solvent such as e.g. B. chloroform, methylene chloride or ethyl ether, and the organic phase is evaporated to dryness. The remaining product of the formula X can continue to be used as is, or it can be further purified by standard methods known per se in the art, such as, for example, column chromatography over silica gel.

In the case of compounds of the formula IX in which both radicals X and Y are hydrogen atoms and R _{2 is} the benzyl radical, can

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the corresponding compound of the formula X can be obtained by catalytic debenzylation using hydrogen and a palladium-on-carbon catalyst. Typically, the reaction is carried out using the hydrochloride salt of the compound X at a temperature of about 50 ⁰ C to 100 ⁰ C, preferably 60 ⁰ C to 75 ⁰ C, and hydrogen pressures of from about 1.4 to 7 kg / cm in the presence of a React ion inert en solvent such as. B. methanol, ethanol, isopropanol, ethyl acetate or mixtures thereof carried out with water. After the hydrogen uptake is complete, the catalyst is removed by filtration and the hydrochloride salt of the product of formula X is precipitated by adding a nonsolvent such as ethyl ether, benzene or hexane. Alternatively, the free base of the formula X can be obtained by evaporating the filtrate from the debenzylation to dryness, partitioning the residue between aqueous alkali, e.g. B. sodium hydroxide, and a solvent such as chloroform or ethyl ether. The free base is then according to standard methods, e.g. B. the methods described above, isolated.

The intermediates of the formula X can be converted to the desired 2-methyl compounds XI by acylation with a chloroformate ester, preferably ethyl chloroformate, and then Reduction of the intermediate 2-alkoxycarbonyl-2,3> 4-, 4-a, 5 »9bhexahydro-1H-pyridoC4-, 3-bJ-indole be converted with lithium aluminum hydride. The reaction between, for example, ethyl chloroformate and the compound of the formula X is under practically anhydrous conditions in the presence of a reaction-inert, organic solvents such as chloroform, methylene chloride, tetrahydrofuran or ethyl ether and preferably in Presence of a tertiary amine such as e.g. B. pyridine, triethylamine or N, N-dimethylaniline carried out. To a solution the compound of formula X in the solvent that

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optionally contains a molar excess of the tertiary amine, an approximately equimolar amount of the chloroformate ester is added. After the addition, the reaction mixture is stirred for a period of up to a few hours. The reaction is usually carried out at or near room temperature, but higher or lower temperatures from about ⁰ ° C. to the reflux temperature of the solvent can also be used. If ethyl chloroformate is used, 2-A * thoxycarbonyl-2,3, 4-, 4a, 5j 9b-hexahydro-1H-pyridoü4,3-b] indole derivative obtained as an intermediate is isolated by methods known per se to the person skilled in the art, z. B. by evaporating the reaction mixture to dryness, distributing the residue between a water-immiscible organic solvent such as ethyl ether, chloroform or dichloromethane and a dilute, aqueous acid such as hydrochloric acid or sulfuric acid. The organic extracts are washed with water, dried and evaporated to dryness in order to obtain the product suitable for further use in the hydride reduction stage.

The reduction is preferably carried out in the presence of an inert gas such as nitrogen or argon and under essentially anhydrous conditions. An about 2-fold to 10-fold molar excess of lithium aluminum hydride is suspended in an ethereal solvent, for example Ithylather or tetrahydrofuran, and the mixture is preferably cooled to a temperature of about 0 C to 10 ⁰ C. The 2-alkoxycarbonyl intermediate obtained as described above is usually dissolved in the same solvent and the solution is added dropwise. The resulting mixture is then allowed to react, usually at about room temperature for a period of about 0.5 to 4 hours, to bring the reaction to practical completion. The excess on

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Lithium aluminum hydride is then decomposed, ζ. Β. by careful addition of water, the resulting mixture is filtered and the I filtrate is evaporated to dryness, in order to obtain the desired product of formula XI, which then, if necessary, according to standard methods known in the art are known per se, can be further purified. Alternatively, the free base XI can be converted into a salt such as, for example the hydrochloride addition salt by adding anhydrous hydrogen chloride to a solution of the base in one Solvents such as ethanol, ethyl ether or mixtures thereof are converted. The precipitated salt can then collected, e.g. B. by filtration.

The free bases of the formula X can also be used as precursor compounds serve for the new compounds of the formula XI, which is illustrated by the following reaction sequence, wherein X and Y, which can be the same or different, are each a hydrogen or fluorine atom, Z is a hydrogen atom, Is fluorine atom or methoxy radical, and η is the number 2 or J.

■ ι

C- (CH ₂ ) ^ COH
(XII)

(XIII) LiAlH

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The acylation of the compounds X to form the intermediates of the formula XIII can be carried out using the acids of the formula XII or the corresponding acid chlorides or acid bromides. When the acids of formula XII are used in the acylation, approximately equimolar amounts of this acid and the compound of formula X are brought into contact in the presence of an inert organic solvent and certain condensing agents known in the art for forming peptide bonds. Such agents include carbodiimides, e.g. B. dicyclohexylcarbodiimide and 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimidhydro chloride and alkoxyacetylenes, e.g. B. methoxyacetylene and ethoxyacetylene. The preferred condensing agent is dicyclohexylcarbodiimide. Examples of solvents that can be used are: dichloromethane, chloroform, tetrahydrofuran, ethyl ether and benzene. Although the reaction can be carried out at a temperature of about -10 ⁰ C to 50 ⁰ C with satisfactory results, a temperature of about 0 ⁰ C to 30 ⁰ C is preferably applied. At this temperature, the reaction is usually complete in a few hours. The product of formula XIII is isolated, for example, by filtering to remove insoluble material and by evaporating the solvent. The product obtained is usually of sufficient purity for use in the next stage.

The intermediate of Formula XIII is then made with lithium aluminum hydride implemented as previously described for the preparation of 2-methyl compounds of the formula XI. That Product of formula VI is also isolated and purified as described above, e.g. B. by Column chromatography on silica gel.

Another method for making the 4-a, 9b-trans compounds of the formula VI in a mixture with the corresponding dehydrated compounds of the formula VII is shown in the following scheme

explained:

809848/0960

: ;-( GL) - ciK ii

O) BIl / ether

(2) H +

; i- (ClI ₂ ) _m -ClI = CH

where X, Y, Z, η and m have the meanings given above ". The reaction with borane in an ether solvent, preferably tetrahydrofuran, and the subsequent treatment with acid is among those previously used for preparation of the 2-benzyl compounds of formula IX carried out given conditions. Products VI and VII are for example separated by column chromatography on silica gel.

The relative amounts of products VI and VII vary depending on the amount of acid, e.g. B. hydrochloric acid, and the time of reflux after the reduction with BH, .THF has taken place. Higher amounts of acid and longer Reflux times favor the dehydrated product of the Formula VII, while smaller amounts of acids and shorter reflux times favor the formation of product VI.

The compounds of the formula VI can also be used as precursor compounds the free bases of the formula X are used. The reaction is carried out so that, for example, ethyl chloroformate used, causing an alkaline hydrolysis, like them

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previously for the debenzylation of compounds of the formula IX, where E ^ is benzyl, has been described to be the free bases of the formula X follows.

The oxidation of the compounds of formula VI using reactants and conditions as they are for selective conversion of secondary alcohols to the corresponding ketones are known, provides the new Products of the following formula:

N- (CH) - ^ n.

(XIV)

wherein X, Y, Z and η have the meanings given above. Examples of such oxidizing agents, which at Potassium permanganate, potassium dichromate and chromium trioxide, the preferred, can be used in this reaction The reagent is chromium trioxide in the presence of pyridine. When performing this reaction with the preferred Eeagens is the starting alcohol of the formula VI in a reaction-inert solvent, for. B. dichloromethane, chloroform or benzene, added to a mixture containing up to a 10-fold molar excess of chromium trioxide and one contains a similar molar excess of pyridine and the mixture is stirred, usually at room temperature, until the reaction is essentially complete. Usually about 15 minutes to 1 hour is sufficient. The product is isolated, e.g. B. by removing insoluble material by filtration, extracting the filtrate with a dilute, aqueous alkali such as sodium hydroxide solution, dry the organic layer and evaporate

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Dry. The remaining product can optionally be further purified, e.g. B. by column chromatography.

The production of the starting materials is described below:

2-Benzyl-5-pkenyl-1,2,3,4-tetrahydro-T-carboline is obtained according to Fischer's indole synthesis using N, N-diphenylhydrazine and N-benzyl-4-piperidone. The mono- or di-fluoro-substituted starting tetrahydro-y ¹ -carbolines of the formula VIII, in which at least one of the best Σ or Y is a fluorine atom and E ~ ^ er is a benzyl radical, are prepared from the corresponding compounds of the formula VIII, in which E ~ ^e ^ ^{J1 is} hydrogen atom, produced by reaction with a benzyl halide such as benzyl bromide in equimolar amounts. The compounds of the formula VIII, Eq = H, required for this purpose are prepared in accordance with the information in US Pat. No. 4,001,263. The starting t et rahydro-T'-carboline V are described in the same publication.

The other starting materials are either commercial products, their preparation is in the chemical literature described in detail or they can be prepared by methods known per se to the person skilled in the art. For example Pheny! hydrazine are commercially available or they will be by reducing the phenyldiazonium salt according to the information provided 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 Eeagenzien or they are according to the method of McElvain and Eorig, J. Am. Chem. Soc., £ 0 0948)> S. 1826, produced. The required 3-benzoylpropionic acids and 4-Benzoylbutyric acids are either commercially available or by modifying the procedure in accordance with "Organic Synthesis", Coll. Vol. 2, John Wiley & Sons, New York, N.Y., 1943, p. 81.

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As described above, the basic according to the invention Compounds form acid addition salts. The basic compounds are converted into their acid addition salts by bringing them together the base is converted with an acid in either an aqueous or a non-aqueous medium. In a similar way results in treatment of the acid addition salts with an equivalent amount of an aqueous base solution, e.g. B. alkali metal hydroxides, Alkali metal carbonates and alkali metal bicarbonates or with an equivalent amount of a metal cation, which forms an insoluble precipitate with the acid anion, the reformation of the free base. That way Reconverted bases can be reconverted to the same or a different acid addition salt.

In utilizing the chemotherapeutic activity of the salts of the compounds according to the invention, it will be taken for granted preferred to use pharmaceutically acceptable salts. Although the insolubility in water, a high Toxicity or lack of crystalline nature either certain type of salt unsuitable or unsuitable for use as such in a given pharmaceutical application can make less suitable, the water-insoluble or toxic salts can be in the corresponding pharmaceutical acceptable bases can be converted by decomposing the salt as previously described, or alternatively they can reconverted to any desired pharmaceutically acceptable acid addition salt.

Examples of acids which provide pharmaceutically acceptable anions are hydrochloric acid, hydrobromic acid, Hydroiodic acid, nitric acid, sulfuric acid, sulphurous Acid, phosphoric acid, acetic acid, lactic acid, citric acid, tartaric acid, succinic acid, maleic acid and gluconic acid.

As previously described, the compounds of the invention are readily adapted for therapeutic use as tranquilizers

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adapted in mammals.

The tranquilizers according to the invention are characterized by relief from schizophrenic states in humans such as hallucinations, hostility, suspicion, emotional or social withdrawal, anxiety, agitation and states of tension. Standard procedures for detecting and comparing the tranquilizing activity of compounds of this series and for which there is an excellent correlation with the efficacy in humans is the antagonism of amphetamine-induced symptoms in the rat test, as described by A. Weissman et al., J. Pharmacol. Exp.Ther., 151 , p. 339 (1966) and by Quinton et al., Nature, 200 , p. 178 (1963).

The tf'-carbolines and the pharmaceutically acceptable salts thereof, which are useful as tranquilizers can be used either as individual therapeutic agents or as mixtures of therapeutic agents are applied. They can be applied on their own, but in general they will applied together with a pharmaceutical carrier, which takes into account the chosen route of administration and is selected according to standard pharmaceutical practice. For example, they can be taken orally in tablet form or capsules containing such diluents as starch, lactose or certain types of clay, etc., be applied. In the form of elixirs or oral suspensions, they can be applied, with the active ingredients are combined with emulsifying and / or suspending agents. They can be injected parenterally, and in this application they or suitable derivatives can be prepared in the form of sterile aqueous solutions. Such aqueous solutions should be appropriately buffered, if necessary, and they should be other dissolved ones Contain substances such as salt or glucose to make the solutions isotonic.

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Although the use according to the invention is directed to the treatment of mammals in general, it is preferred Use in humans. As is readily apparent, the doctor can ultimately determine the dosage that is right for one is most suitable for a particular patient; this will vary with the age, weight, and response of that particular patient Patients, as well as the nature and extent of symptoms and the pharmacodynamic properties of the particular Means to be applied. In general, only small doses are applied at the beginning, with gradual doses The dose is increased until the optimal level is determined. It is often found that with oral Application of the agent larger amounts of active ingredient are required to achieve the same effect, as it is achieved by a smaller amount in the case of parenteral administration.

Taking into account the factors described above, it is believed that the daily dosage of the invention Compounds in humans approximately 0.5 to 100 mg with a preferred range of 1 to 25 mg gives an effective tranquilizer effect. In those individuals in whom the invention Compounds have a longer effect, the dose can be 5 to 125 mg per week, applied in one or two subdivided single doses. These values are for illustrative purposes only and can of course be used in individual cases higher or lower dose ranges may be advantageous.

All compounds of the formulas II, III and IV have at least two asymmetric centers that result from the reduction of the 4a, 9b double bond to the trans-fused system. The invention includes the racemates as well as single enantiomers. If the substituent in

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the 2-position (P) is an existent in stereoisomeric forms Including grouping, the compounds according to the invention include all master isomers resulting therefrom.

The invention is further illustrated by the following examples explained.

example 1

dl-trans-2-benzyl-2, J, 4,4a, 5 j ^ b-hexahydro - ^ - phenyl-IH-pyrido-

[4-, 3-b I-indole hydrochloride

To a at ⁰ ° C stirred solution of 0.14 to 0 mol borane in 150 ml of tetrahydrofuran in a vessel equipped with magnetic stirrer, thermometer, condenser and addition funnel, and maintained under a nitrogen atmosphere for three-necked flask was added a solution of 23.9 g "0.071 mol 2- Benzyl-5-phenyl-1,2,3,4-tetrahydropyridoC4,3-b] -indole in 460 ml of dry tetrahydrofuran was added. The addition was carried out at such a rate that the reaction temperature remained ^{below 9 ° C.} After the addition was complete, the resulting mixture was heated to reflux temperature and held at that temperature for 1 hour. The solvent was then evaporated off in vacuo to give a white, solid mass which was suspended in 40 ml of dry tetrahydrofuran and initially heated slowly together with 180 ml of a 1: 1 volume mixture of acetic acid and 5N hydrochloric acid. The resulting suspension was refluxed for 1 hour and then cooled. Evaporation of the tetrahydrofuran and part of the acetic acid gave the precipitate of a white solid which was separated by filtration and washed with water. The solid was resuspended in tetrahydrofuran, filtered, washed with ethyl ether and air dried to give 16.7 g (63%) of the desired

809848/0960

trans isomers were obtained; Έ. 256-260 ⁰ C.

Evaporation of the mother liquor gave a further 7> 2 g of des Product which were contaminated with a small amount of the cis-isomer.

When repeating the procedure described above, however, using the correspondingly substituted one 2-benzyl-5-phenyl-1,2,3,4-tetrahydropyridoC4,3-b] indole as the starting material, the following 4a, 9b-trans compounds were similarly used in the form of their hydrochloride salts obtain:

J. O D

H ρ- fluor FH

F £ -fluor

X Y

H c) fluorine

F m-fluor

F o-fluor

Example 2

dl-trans-5-ehenyl-2,3,4, 4a, 5, 9b-hexahydro-1H-pyridoC 4,3-bu-indole

A suspension of 4.17 g of dl-trans-2-benzyl-5-phenyl-2,3,4,4a-5 _i 9'b-hexahydro-'1H-pyrido [4,3-b] -indole hydrochloride in 150 ml of absolute ethanol was hydrogenated at 3 »5 kgf / cm and 60-70 ⁰ C using 1.0 g of 10% Pd / C catalyst over a period of 2 hours. The catalyst was removed by filtration

809848/0960

removed and sufficient ethyl ether was added to the filtrate to precipitate the hydrochloride of the desired product; Yield = 2.76 g (87%); F. 235-237 ⁰ C.

The hydrochloride salt was converted to the free base by partitioning between ether and dilute sodium hydroxide solution. The ether layer was dried over sodium sulphate and evaporated, the compound named in the title being obtained in a yield of 97 % ; F. 74-76 ⁰ C.

Example 3

dl-trans-8-fluoro-5- (p-fluorophenyl) -2- [4-hydroxy-4- (p-fluorophenyl) -butyl 3-2,3,4,4a, 5,9b-hexahydrO-1H-pyrido [4,3-b] -indo1-hydrochloride, and

dl-trans-8-fluoro-5- (p-fluorophenyl) -2- [4- (p-fluorophenyl) -3-butenyl1-2,3,4,4a, 5 j 9b-hexahydro-1H-pyrido [4,3-b] -indole hydrochloride

In one equipped with a magnetic stirrer and dropping funnel and 1000 ml reaction containers kept under a nitrogen atmosphere, there was added 177 ml of 0.94 M borane tetrahydrofuran solution entered. The solution was cooled in an ice bath and the cold solution was added to over a period of time a solution of 25 g = 0.0555 mol over a period of 30 minutes 8-fluoro-5- (p-fluorophenyl) -2- [4-hydroxy-4- (p-fluorophenyl) butyl] -2,3,4,5-tetrahydropyrido [4,3-b] indole added in 295 ml of tetrahydrofuran. The resulting mixture was stirred at ambient temperature for 20 minutes, then was it refluxed for 2 hours. The reaction mixture was cooled and concentrated in vacuo, leaving a liquid Residue was obtained. A mixture of 50 ml each of acetic acid and 5N hydrochloric acid was added to this residue added, whereupon a vigorous evolution of gas occurred.

809848/0960

The mixture was refluxed for 1 hour, cooled to room temperature and filtered. The filtrate was cooled in ice and made alkaline by the addition of 50% w / w sodium hydroxide solution. The basic mixture was extracted twice with 150 ml portions of chloroform, the combined organic layers were dried over magnesium sulfate and evaporated to dryness in vacuo to give 25 g of a yellow, foamy pesticide. Thin layer chromatography on silica gel using a solvent system of 1: 1 volumes of hexane / ethyl acetate gave two products. The foamy solid was chromatographed on a column of silica gel, eluting with 1: 1 volumes of hexane / ethyl acetate and monitoring the fractions by Tl3 (thin layer chromatography). The only the more rapidly migrating product, ie 8-fluoro-5- (p-fluorophenyl) -2- [4- (p-fluorophenyl) -3-butenyl] -2,3,4-, 4a, 5> 9b-hexahydro Fractions containing -1H-pyrido [4,3-b] indole were evaporated to dryness, taken up in acetone and converted to the hydrochloride salt by the addition of anhydrous hydrogen chloride in acetone, the resulting white solid being collected by filtration and dried. There was added 1.5 g of 3-Butenylverbindung obtained with F. 270-273 ⁰ C.

Only the more slowly migrating 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-containing fractions were concentrated, taken up in ethyl ether and the hydrochloride salt in transformed by adding anhydrous hydrogen chloride to give 10.8 g of this product with F. 241-245 ⁰ C obtained .

The proportion of the more rapidly migrating 3-butenyl compound is up to 100% by appropriately increasing the acidity and the period of reflux heating in the mixture of acetic acid / Hydrochloric acid increased.

809848/0960

Example 3A

When the procedure of Example 3 is repeated using 8-fluoro-5- (o-fluorophenyl) -2- [4-hydroxy-4- (p-fluorophenyl) butyl] -2.3> 4.5- Tetrahydropyrido [4,3-t> I-indole as a starting material became the more rapidly migrating component in silica gel chromatography as trans-8-fluoro-5- (ofluorophenyl) -2- [4- (p-fluorophenyl) -3-'butenyl] -2 _i 5,9bhexanhydro 3,4,4a-1H-pyrido [4,3-b] indole obtained with F. 141-142 ⁰ C. The more slowly migrating component was identified as trans-8-fluoro-5- (of luophenyl) -2- [4-hydroxy-4- (pf luophenyl) butyl] -2,3,4,4a-5,9b-hexahydro- 1H-pyrido [4,3-b] indole identified with F. 195-197 ⁰ C.

Example 4

Using the appropriate compounds of Formula V as starting materials in the procedure of Example 3, were the 4a, 9b-trans products of the formulas VI and VII given below are obtained in the respective cases and separated. at the products of the formulas nVII means m = η -1.

N- (CH-) CH-2 η,

OH

(V)

80984 8/096

. N- (CH ₀ ) CH = CH

Z m ■

(VII)

3 3 3 3 3 4th 4th 4th 4th 4th 4th 4th 4th 4th 3

X F F H F H F F F F. F H U Ii H H

Y ·

£ -fluoro

£ -fluoro

£ -fluoro

il

£ -fluoro

£ -fluoro

p-fluor

£ - fluor

£ -fluoro

£ -fluoro

o ^ -f luor

m-fluor

p-mcthoxy _o-mcthoxy £ -Cluoro £ -fluoro p-methoxy H .

o_-fluoro in-raethoxy £ -fluoro

Ii

Jj-fluoro £ -fluoro

3 II ra-fluorine in-fluorine

3 F £ - £ luor p-methoxy

3 H m-fluor H

4 F £ -fluoro £ -fluor

4 F ra-fluoro E-methoxy

809848/0980

Example 5

dl-trans-8-fluoro-5- (p-fluorophenyl) -2,3,4, 4a, 5, 9b-hexahydro-

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

A) To a solution of 5-6 g = 12.4 mmol of dl-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 in 40 ml of toluene were given 5-3 ml = 55-7 mmol of ethyl chloroformate. The resulting mixture was refluxed overnight and then evaporated to dryness to give a gummy product as a residue. To this gummy product, 200 ml of a 9: 1 volume mixture of ethanol / water was added. After the gummy product was dissolved, 15 g of potassium hydroxide was added and the resulting mixture was refluxed overnight. The solvent was evaporated in vacuo and the residue was partitioned between water and chloroform. The organic extracts were washed with water, dried over sodium sulfate and evaporated to dryness. The remaining oil was taken up in ethyl acetate and passed through a silica gel column, eluting first with ethyl acetate to remove by-products and then eluting the desired product with a 1: 1 volume mixture of ethyl acetate / methanol. The fractions containing the compound named in the title were combined and evaporated to dryness to give 1.6 g (43 %) of a yellow gummy product which crystallized on standing; F. 115-117 ⁰ C.

B) Alternatively, dl-trans-2-benzyl-8-fluoro-5- (p-fluorophenyl) 2 ϊ 3 j 4, 4a, 5, 9b-hexahydro-1 H -pyrido [4,3-b] indole hydrochloride in the presence of excess ethyl chloroformate or the corresponding methyl, isopropyl or η-butyl chloroformate ester boiled under reflux and then hydrolyzed and worked up according to the procedure described above, to the in the connection named in the heading.

809848/0380

Example 6

Using the appropriate starting materials in in each case and using the procedures of Examples 5A or 5B, the following products became more comparable Way to get:

dl-trans-5- (p-fluorophenyl) -2,3,4,4a, 5 ί 9b-hexahydro-1H-pyrido [4,3-b] indole,

dl-t rans-Ö-Fluor- 5-pheny 1-2,3,4 ^, 5,9b-hexahydro-1H-pyrido [4,3-b] -indole,

dl-trans-5- (o-fluorophenyl) -2,3 »4-, 4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole,

dl-trans-5- (o-fluorophenyl) -8-fluoro-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-bl-indole,

dl-trans-5- (m-fluorophenyl) -8-fluoro-2,3,4,4a, 5 »9b-hexahydro-1H-pyrido [4,3-b] indole,

dl-trans-5- (m-fluorophenyl) -2.3 »^ 14-a, 5, 9b-hexahydro-1H-pyridoC4,3-b] -indole.

Example 7

dl-trans-8-fluoro-5- (p-fluorophenyl) -2-methyl-2,3,4,4a, 5,9b-

hexahydro-1H-pyrido C4,3-b] indole hydrochloride

A) In one with stirrer, dropping funnel and nitrogen inlet equipped 25 ml flask were 573 mg = 2.0 mmol of 8-fluoro-5- (p-fluorophenyl) -2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] -indole, Filled in 8 ml of dichloromethane and 0.323 ml = 4 mmol of dry pyridine. The resulting solution was added at room temperature a solution of 0.219 ml = 2.3 mmol of ethyl chloroformate dropwise added. After the addition was complete, the mixture was stirred for 1 hour. The mixture was then in vacuo evaporated to give a gummy product as residue. This was between 10 ml of 10% hydrochloric acid and 25 ml of ether distributed. The organic layer was washed with 10 ml of water, dried over magnesium sulfate and

809848/0980

evaporated to dryness, leaving 707 mg of 8-fluoro-5- (p-fluorophenyl) - ^ - ethoxycarbonyl- ^, 3, 4,4a, 5,9b-hexahydro-1H-pyrido- [4,3-bJ-indole were obtained, which were used in the next stage.

B) In one with a magnetic stirrer, dropping funnel and nitrogen inlet tube 100 ml flask provided with 10 ml of ethyl ether and 524 mg = 13.8 mmol lithium aluminum hydride entered. The suspension was cooled with the aid of an ice bath. After stirring under a nitrogen atmosphere for 5 minutes a solution of 707 mg = 1.97 mmol of the product was obtained the previous step A) in 5 ml of ether dropwise during added over a period of 5 minutes. The resulting mixture was then stirred at room temperature for 1 hour, then 3 g of anhydrous sodium sulfate were added, followed by the slow addition of 1 ml of water. After stirring for 30 minutes, the resulting mixture was filtered and the collected white solid was washed with ether. The filtrate was evaporated to dryness, redissolved in ether, and it became a saturated solution of anhydrous Hydrogen chloride in ether was added until the precipitation was complete. The obtained precipitate was through Filtration recovered to give 481 mg of the title compound.

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, 146, 109, 95, 74, 58 (109%)

¹ HNMR (CDCl ₃ ), i: 1.84-2.50 (4H, m), 2.52 (3H, s), 2.98-3.26 (3H, m), 3.46-3, 64 (1H, m), 6.50-7.46 (7H, m)

809848/0980

Example 8

In the implementation of the products obtained in Example 6 with ethyl chloroformate in the presence of pyridine and solvent, as in Example 7-Ä. "and reduction of the obtained 2-lthoxycarbonyl derivative as in Example 7B described the following racemic 4-a, 9b-trans compounds obtained in a comparable way:

X Y H £ -fluoro F. H U o-fluorine F. £ -fluoro F. m-fluor H m-fluor

809848/0980

Example 9

dl-trans-2- (4-hydroxy-4-phenylbutyl) -5-phenyl-2,3,4, 4a, 5, 9b-

hexahydro-1H-pyrido [4,3-b] -indolhydrο chloride

A) To the suspension obtained from the mixing together 865 mg = 4.20 mmol of dicyclohexylcarbodiimide and 748 mg = 4.20 mmol of 3-benzoyl-propionic acid in 30 ml dichloromethane at 0 ⁰ C, was added 1.0 g = 4.0 mmol of dl-trans-5-phenyl-2,3,4,4a, 5,9b-hexahydro-1H-pyridoC4,3-b] -indole in 10 ml of the same solvent were added. The resulting mixture was stirred over a period of 2 hours and allowed to warm to room temperature. After cooling again to 0 ⁰ G, the reaction mixture was filtered, washed with dichloromethane, and the filtrates were evaporated, leaving a residue of dl-trans-2-L (3-benzoyl) propionyl] -5-pkenyl-2,3 , 4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole was obtained, which was used in the next stage without further purification.

B) The residue obtained from the previous step was dissolved in 50 ml of tetrahydrofuran and heated to reflux. A filtered solution of lithium aluminum hydride in like Solvent was added until gas evolution ceased (molar excess) and the resulting mixture became stirred under reflux for 5 to 10 minutes, then cooled. There was 17 g of anhydrous, powdered sodium sulfate added, then 0.5 ml of water. The resulting mixture was stirred at room temperature for 30 minutes, filtered, and the filtrates were evaporated to dryness in vacuo.

The residue was chromatographed on a column which Contained 80 g of silica gel, with 4: 1 v / v. Ethyl acetate / methanol was eluted to remove the free base of the Obtain the heading compound after evaporation of the solvent. The free base was converted into the

809848/0960

Hydrochloride salt by dissolving in ether and adding a saturated solution of anhydrous hydrogen chloride in ether until completion of the precipitation, filtration and drying, whereby 1.04 g of product were obtained with F. 222-224 ⁰ C.

IR spectrum (KBr) µ: 2.97, 3.4-3, 4.00 (broad), 6.25, 6.68, 6.88, 7.51, 7.96, 8.18, 8 .45, 9.82 mass spectrum M / e: 398, 292, 263, 249, 220, 207, 192 (100 %) ;
UV spectrum (methanol) λ _v 245 (£ = 0.653 x 10 ⁴ ),

j. IHcLjC

270 (£ = 0.914 χ 1 (T ")

Example 10

Using the appropriate starting material in each case, this from the examples 2 and 5 and the corresponding 3-benzoylpropionic acid were selected as follows dl-trans compounds according to the procedure of the example 9 manufactured. The products were isolated as the hydrochloride salts, unless the exception is noted.

X Y Z F. ⁰ C Yield (%) F. F. H 220-223 18th H H F. 239-245 39 H H GH ₃ O amorphous solid
(a) 54- F. F. CH-, 0 45-48.5 (b) 31

809848/0960

_ 39 -

(a) mass spectrum, m / e: 428, 411, 263 (100 ⁰ Jo) , 220, 206, 204;

IR spectrum (KBr), ju: 2.98, 3.42, 4.0? (wide), 6.20, 6.26, 6.70, 6.88, 8.04, 8.54, 9.77, 12.05

Cb) Melting point and yield values refer to the free base.

Example 11

Using the corresponding dl-trans-hexahydro-1H-pyrido [4,3-b] -indole, this being selected from the products of Examples 2, 5 and 6, and accordingly substituted 3-benzoylpropionic acid or 4-benzoyl butyric acid the following compounds were obtained following the procedure of Example 9:

3 F £ -fluoro in-fluor

3 F p-fluoro E-methoxy

3 F H £ - fluor

3 H £ -fluoro jv-methoxy

3 II o-Cluor in-muthoxy

3 F U H

3 II m-fluor II

3 H H m-fluor

4 F £ -fluor £ -fluQr

4 F £ -fluoro p-methoxy

4 F £ -fluor II

4 F H H

4 · F H m -metlioxy

4 II £ - fluor H

809848/0980

A U ra- £ luor t ^ -fluor

4 Η £ -fluoro £ -methoxy

4 H H £ -methoxy

3 11 j) -fluoro jn-fluor

3 Ll ^ 3-fluorine o-fluorine

3 F m-fluoro £ -fluoro

3 H m-i luor]> - fluor

Example 12

dl-trans - ^ - Ehenyl ^ - l3- (p-fluorobenzoyl) propyl] -3,4,4a, 5 * 9b-

hexahydro-1 H -pyrido [4,3-b . -indoUiydro chloride

In one equipped with a magnetic stirrer and under reaction vessel held in a nitrogen atmosphere of 25 ml, 0.828 ml = 8.0 mg = 10.3 mmol dry Pyridine and 10 ml dichloromethane entered. 517 mg = 5 * 17 mmol of chromium trioxide were added to the solution, and the resulting dark red suspension was stirred for 15 minutes at room temperature. A solution of 359 mg = 0.862 mmol dl -trans-5-phenyl-2- [4-hydroxy-4- (p-fluorophenyl) butyl] 2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-bj -indole in the form of the free base in 5 ml of dichloromethane were added all at once. The mixture of reactions quickly turned into one brown suspension around. This was stirred at ambient temperature for 30 minutes. The insoluble material was removed by filtration, washed with dichloromethane, and the combined filtrates and washes were removed extracted with 20 ml of 10% sodium hydroxide solution. the organic layer was dried over MgSO ^ and in vacuo evaporated to dryness to give a gummy product. This rubbery product has been through. Purified column chromatography on silica gel, eluting with a 1: 1 volume mixture of hexane / ethyl acetate. the Fractions containing the desired product were combined, evaporated to a yellow, gummy product,

809848/0960

the gummy product was taken up in ethyl ether and treated with anhydrous hydrogen chloride. The resulting suspension was evaporated to dryness and slurried with 3 ml of cold dichloromethane. It formed a colorless solid which was collected by filtration and dried to give 20 mg of the compound of the title with F. 244 to 246.5 ⁰ C were obtained.

Example 15

dl-trans-8-fluoro-5- (p-fluorophenyl) -2- [3- (p-liiorb enzoyl) -propyl] -2,3,4,4a, 5 »9b-hexahydro-1H-pyrido [4,3 -b] -indole-

hydrο chloride

In a 20 ml dichloromethane and 1.76 ml = 21.9 mmol pyridine 100 ml flask containing 1.09 g of chromium trioxide was added, and the resulting dark suspension was stirred at ambient temperature for 15 minutes. Then all of a sudden a solution of 824 mg = 1.82 mmol of dl-trans-8-fluoro-5- (p-fluorophenyl) -2- [4-hydroxy-4- (p-fluorophenyl) -butyl! -2,3,4-4a, 5 »9b-hexahydro-1H-pyridoL4,3-b1-indole in the form of the free base (obtained from the hydrochloride salt by making it alkaline an aqueous solution with sodium hydroxide, extraction with dichloromethane and evaporation of the extracts to dryness) added in 10 ml dichloromethane. The resulting red-brown suspension was at ambient temperature for 1 hour stirred and worked up according to the procedure used in Example 12, 25 mg of the desired product with Mp 260-263 ° C.

Example 14

Using the appropriate starting material selected from those obtained in Examples 9-10 and 11 Products, and performing the oxidation according to the procedure of Example 12, the following 4a, 9b trans compounds were obtained manufactured:

809848/0980

X • Y Υ_ _Z η F. £ -fluoro H 3 H Il p_-fluor 3 H H p_-methoxy 3 F. p-fluor p-mcthoxy 3 11 jp_-f luor £ -mothoxy 3 II £ -fluoro m-intithoxy 3 ι ·· II jj-fluor 3 F. H II 3 H II H 3 F. £ - fluor m-fluor 3 H ni-fluor Il 3 F. £ -fluoro £ -fluoro 4th F. p-fluor p_-mathoxy 4th F. o-fluorine H 4th F. H H 4 · F. II m-meclioxy 4th H p-fluor H 4th Ii ra-fluor o- fluor 4th H o-fluorine jr-mcthoxy 4th H II o-raethoxy 4th Il p-fluor jv-f luor 3 II o-fluorine £ -fluoro 3 F. m-fluor £ -fluoro 3 H m-fluor £ -fluoro 3

80984S / 0960

Example 15

dl-trans-8-fluoro-5- (p-fluorophenyl) -2- [4-hydroxy-4- (p-fluorophenyl) butyl 3 -2,3,4,4a, 5,9b-hexahydro-1H-pyridoC 4,3-bj indole acetate

5 g of dl-trans-8-fluoro-5- (p-fluorophenyl) -2- [4-hydroxy-4- (p-f luophenyl) -butyl3 -2,3,4,4a, 5,9b-hexahydro-1H-pyrido L 4,3-bl indolhydrοchloride in 75 ml of water were mixed with 3 ml of water, which contained 1.0 g of sodium hydroxide, and the released compound in the form of the free base was in 150 ml of diethyl ether extracted. The ether layer was separated, dried over magnesium sulfate and treated with 1 ml of glacial acetic acid. The organic solvent and the excess the acetic acid was removed under reduced pressure and the residue was triturated with hexane and filtered.

In a similar manner, other acid addition salts, particularly those which are pharmaceutically acceptable, can be prepared will.

Example 16

Trials and results

The effects of the compounds according to the invention on salient, Amphetamine-induced symptoms were examined in rats using a grading scale based on the model reported by Quinton and Halliwell and Weissman. Groups of five rats were made placed in a covered plastic cage with the approximate dimensions 26 cm 42 cm χ 16 cm. After a short In the cage acclimatization period, the rats in each group were treated subcutaneously (s.c.) with the test compound. They were then treated with d-amphetamine sulfate 1 hour, 2 hours and 24 hours later at a dose of 5 mg / kg intraperitoneally (i.p.)

809848/0980

treated. One hour after the amphetamine administration, each rat was observed for the characteristic amphetamine behavior of movement around the cage. On the basis of the dose-response data after the amphetamine, it was possible to determine the effective dose of the compound required for antagonism or the blocking of the characteristic amphetamine behavior of cage movement in 50% of the rats examined (ED ™) was. The selected classification time coincides with the peak effect of amphetamine, which is 60 to 80 minutes after treatment with this agent.

Using the procedure previously described, the following 4a, 9b-trans compounds for their ability studied to block the behavioral effects of amphetamine, with the results as ED ^ Q values in mg / kg for the times given are:

NO

809848 / 096Q

ED ₅ O (mg./kg.) Tt

Η ·

IC YR 1 h. 2 h 24 h

HH CH ₁ -CH- (CH ₀ ), - 0.032-0.1 0.032-0.1 0.1-0.32 (D.

Oh _λ

H ^ H P-fC, H.CH- (CH ₀ ), - 0.1-0.32 0.1-0.32 0.1-0.32

■ * - O 4 | I J ^ -s

Oh %

H H * p-CH, 0C, H, CH- (CH,), - 0.1-0.32 0.1-0.32 -1.0 to

* - 3 D H \ 2 J (D

OH ^ ^-

° * HH P-FC-HC- (CH ₀ ) .- -0.32 0.1-0.32 -0.32 £ j

O * - 6 4 || i- 3 0q

CD 0 ^v - ^

^ ■ F 2 ^"fluorine-CH ₃ - - ⁰ · ¹ 0.1-0.32> 3.2

? f F 2- ^fluoro CH ₁ -CH- (CH ₀ ) - 0.1-0.32 0.1-0.32 <0.32

a> F o-fluor O-TCsH ₁ CR- (CU ₀ ) , - <0.32 <0.32 <0.32

o ~ ^{6 H} l ²

OH
F 2- ^fluoro '2- ^FC 6 ^H 4 ^CH " ^(CH 2 ⁾ 3 ~ 0.032-0.1 0.032-0.1 0.032-0.1

OH

F ^ p-fluoro P-FC-H-CH = CH- (CH ₀ ), - 0.32-1.0 <0.32 <0.32 ^ N3

F £ -fluoro 2- ^FC ₆ ^I _A ^{CH: = CH} - ( ^CH 2 ⁾ 2 ~ ¹⁰ 3.2-10 3.2-10 ^

F ^{2-fluoro 2-CH} 3 ^{H 0c} o 4 ^{ClI = CH} ~ ^{(CH 2)} 2 "^ ^{1" 3} - ^{2 <Y <3} "i ^

F 2 ~ f ^ ^uor 2 ~ ^CH 3 ^0C ft ^H A ^C ^ ~ i ^CH 2 ^ 2 ~ 0.1-0.32 <0.1 <0.32 CD

OH ⁰ ^

^£ " ^{6 4} II 0

• C-OO

co σ> ο

, (Ο (O

H H H H

C ₂ H ₅ C ₆ H ₅ CH ₂ -

8-? Fluoro -5- (p_-fluoro-phenyl) -2- [A-hydroxy-A- (p-fluoro-phenyl) -bucyl] -1, 2,3,4-tetrahydro-Y-carboline (e)

Navane

po

32 ED ₅₀ (nig./kg.) 24 hours lh .0 2 H > 32 3.2-32 > 3 .2 NT ^Cd) -1.0 > 3 .2 > 3.2 -10 3. 2-32 > 10 3.2-10 3. 2-10 0.32-1.0 0.1-0. 0. 1-0.32 > 32 0.32-1 > 1 0

Remarks:

(a) The corresponding 4a, 9b-cis analog had a -v56 mg / kg at 1h

(b) ED ₅₀ at 48h <0.32; 72 h <0.32

(c) U.S. Patent 3,991

(d) not investigated

(e) U.S. Patent 4,001

(f) cis -9-C3- (4-methyl-1-piperazinyl) propylidene] -2- (dimethylsulfonamido) ■ thioxanthene. U.S. Patent 3,310,553.

CD H · CO ti H-CD H

_Λ

cn

Hi

Cf

co

CKi

Example 17
Tablets

Tablet mass was made by mixing the following ingredients produced in the specified weight ratios:

Sucrose, USP 80.3 tapioca starch 13.2

Magnesium stearate 6.5

Sufficient trans-8-fluoro-5- (fluorophenyl) -2- [4- (p-fluorophenyl) -4-hydr oxybutyl1-2,3,4,4a-5,9b-hexahydro-1H-pyrido [4,3-b] -indole hydrochloride mixed in to tablets with 1.0; 2.5; Get 5 * 0 and 10 mg of active ingredient per tablet. The compositions were compressed in a conventional manner into tablets each weighing 360 mg.

Example 18
Capsules

A mixture was made with the following ingredients:

Calcium carbonate, USP 17.6

Dicalcium phosphate 18 »8

Magnesium trisilicate, USP 5 »2

Lactose, USP 5.2

Potato starch 5 ₅ 2

Magnesium stearate 0.8

A second portion of 0.35 g magnesium stearate and sufficient trans-5-phenyl-2- (4-hydroxy-4-phenylbutyl) -2,3,4,4a, 5 »9t» -hexahydro-1H-pyrido [4,3-b] -indole hydrochloride added to make capsules which

809848/0960

1.0; 2.5; Contained 5.0 and 10 mg of active ingredient per capsule. The compositions were conventional Hard gelatin capsules filled in an amount of 350 mg per capsule.

Example 19
suspension

A suspension of trans-8 -]? Fluoro-5- (p-fluorophenyl) -2-C 4-hydroxy-4- (p-methoxyphenyl) butyl] -2,3, 4-, 4a, 5, 9b-hexahydro-1H-pyridoC4,3-b] indole acetate was made with the following composition:

active ingredient (g) 25.00 70 # aqueous sorbitol (g) 741.29 Glycerin, USP (g) 185.35

Acacia Gum (10% solution) (ml) 100.00 polyvinylpyrrolidone (g) 0.50

Distilled water in sufficient quantity to fill up
on 1 1.

Various sweeteners and flavorings have been added to this suspension to improve the taste of the suspension to improve. The suspension contains approximately 25 mg of active substance Means per ml.

Example 20

Sesame oil was sterilized by heating to 120 ^{° C. for 2 hours.} A sufficient amount of pulverized trans-8 -]? Luoro-5- (p-fluorophenyl) -2- [4- (p-fluorophenyl) -4-hydroxybutyl 3 -2,3,4, 4a, 5, 9t> -hexahydro-1H-pyrido [4,3-b] -indole hydrochloride was added to produce a 0.025% strength by weight suspension. The solid was thoroughly dispersed in the oil using a colloid mill.

Then through a sieve with a mesh size of 0.15-0.0G mm filtered and filled into sterile ampoules and melted.

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Claims (23)

DR. A. VAN DERWERTH DR. FRANZ LEDERER REINER F. MEYER DlPL-ING. (1934-1974) DIPL-CHEM. DIPL-ING. 8000 MUNICH 80 LUCILE-GRAHN-STRASSE 22 TELEPHONE: (089) 472947 TELEX: 524624 LEATHER D TELEGR .: LEATHER PATENT March 28, 1978 P.C. (Ph) 5874 PFIZER INC. East 42nd Street, New York, N.Y. 10017, United States Patent claims y 'Trans-2-substituted-5-aryl-2,3, ⁱ J-, 4-a, 5i9t-liexaliydro-'IH ^ pyrido L ⁱ 4- «3 ~ b J""i indole derivatives in the form of the snantxomers or Eacemate of the following formula: ι U; Sat., 8098 ^ 8/0980 " ORIGINAL iNSPECTEO -Z- and their pharmaceutically acceptable salts, in which the hydrogen atoms bonded to the carbon atoms in the 4a and 9b positions are in the trans arrangement to one another and X _x , and Y _x ., which may be the same or different, are a hydrogen atom or a fluorine atom, η is the number 3 or 4, M is one of the radicals -C- or -CH-, and Z _x denotes a hydrogen atom, fluorine atom or the methoxy radical. 2. Trans-2-substituted-5-aryl-2,3,4, 4a, 5, 9t> -hexahydro-1H-pyrido-4,3-b> indole derivatives in the form of the enantiomers or racemates of the following formula: «7 N- (CH ") CH = CH- _fa ι 2 m · \\ // and their pharmaceutically acceptable salts, in which the hydrogen atoms bonded to the carbon atoms in the 4a or 9b positions are in the trans arrangement to one another and X _x , and Y _x ., which may be the same or different, are a hydrogen atom or a fluorine atom , m is the number 2 or 3 and Zo is a fluorine atom or the methoxy radical. 3. Trans-2-substituted-5-aryl-2,3,4,4a, 5 _T 9 "b 1H-pyridoL4,3-b] -indole derivatives in the form of the enantiomers or racemates of the following formula: 8098A8 / 0S60 ^Y 2 and their pharmaceutically acceptable salts, wherein the
to the carbons in the 4a and 9 "b positions
bonded hydrogen atoms in the trans arrangement
exist to each other and X ^ and Ί. ^, which are equal or
may be different, are a hydrogen atom or a fluorine atom, provided that when one of the radicals Xo
and Yo ^e i ⁿ hydrogen atom, the other represents a fluorine atom. 4. A compound according to claim 1, characterized in that the rest qtj M has the meaning -CH- and η is the number 3. 5. Compound according to claim 4-, characterized in that Xy, and Jy, are a hydrogen atom and Zy, is a p-fluorine atom. 6. A compound according to claim 4, characterized in that Xy, and Xy, are each a fluorine atom and Zy, is a p-fluorine atom. 7. A compound according to claim 6, characterized in that Yy is a p-fluorine atom. 8. A compound according to claim 6, characterized in that Y ^ is an o-fluorine atom. 9. A compound according to claim 4, characterized in that X ^ and Y ^ are each hydrogen atoms and Z ^ is a
is p-methoxy radical. 809848/096 10. A compound according to claim 4, characterized in that Xy \ is a fluorine atom, Y ^ is a p-fluorine atom and Z ^ is a p-methoxy radical. 11. A compound according to claim 4, characterized in that X ^, Y ^ and Z ^ j are each hydrogen atoms. 12. A compound according to claim 4, characterized in that X ^ is a fluorine atom, Y ^ is a p-fluorine atom and Z ^ is a Is hydrogen atom. 13. Compound according to Claim 1, characterized in that the residue q Il M has the meaning -C- and η the number 3 1st. 14. A compound according to claim 13, characterized in that Xy, and Y- are each a hydrogen atom and Z- is a p-fluorine atom. 15. A compound according to claim 13, characterized in that X- is a fluorine atom and Y- and Zy. are each a p-fluorine atom. 16. A compound according to claim 2, characterized in that X- and Y- are each a fluorine atom, Zo is a p-fluorine atom and m is the number 2. 17. A compound according to claim 16, characterized in that Y- is p-fluorine atom. 18. A compound according to claim 16, characterized in that Y ^ is an o-fluorine atom. 19. A compound according to claim 2, characterized in that Xy is a fluorine atom, Y- is a p-fluorine atom, Zo is a p-methoxy radical and m is the number 2. 809848/0960 20. A compound according to claim 3 »characterized in that
that Xq is a fluorine atom and Y £ is a p-fluorine atom. 21. As a tranquilizer active drug, characterized by a content of a tranquiUierenden amount of a A compound according to claim 1 and optionally pharmaceutically acceptable carriers and / or diluents. 22. As a tranquilizer active drug, labeled by retaining a tranquilizing amount of a compound according to claim 2 and optionally pharmaceutically acceptable carriers and / or diluents. 23. As a tranquilizer active drug, labeled by a content of a tranquilizing amount of a compound according to claim 3 and optionally pharmaceutically acceptable carriers and / or diluents. 8098A8 / 0960