DE2822465C2 - 2-substituted trans-5-phenyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole derivatives and medicaments containing them - Google Patents

Description

O OH

I! Il

- C— or -CH—

or η is the number 2 when M is the vinylene group and Z _{1 is} a hydrogen or fluorine atom or the methoxy group and their pharmaceutically acceptable salts.

2. Medicament, characterized by a content of a compound according to claim 1 together with pharmaceutically acceptable carriers and / or diluents.

The invention relates to certain 2-substituted trans-5-phenyl-2,3,4,4a, 5,9b-hexahydro-1 H-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 In the early 1950s, great efforts were made to find other tranquilizers or tranquillants undertaken with improved biological profiles, several of which are γ-carboline derivatives based on are also known in the art as derivatives of pyrido [4,3-b] indole.

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

US Pat. No. 3,983,239 describes hexahydro-y-carbolines of the following formula:

l / \ * ■ Λ N- (CH ₂ J ₃ CO-

wherein R ^{1 is} a methyl or ethyl radical and R ^{2 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-γ-carboline ring from a 1,2,3,4-tetrahydro-γ-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 which are stated to be useful in the treatment of schizophrenia.

US Pat. No. 3,991,199 discloses hexahydropyrimido [4,3-b] indoles and their pharmaceutically suitable ones Salts, described, useful as analgesics and sedatives, some of which are tranquilizers, some

as muscle relaxants of interest, and many of these compounds exhibit hypotensive activity; the described- B

These compounds have the following formula: B

Ν— R "

wherein the hydrogen atoms bonded to the carbon atoms in the 4a and 9b positions are in a trans arrangement to one another, and wherein when Y "= -H, X" = -H, -Cl, -Br, -CH ₃ , -tert. -C ₄ H ₉ or - OCH ₁ , and when V = - CF ₃ , X ^s = - H and R "has the meaning: hydrogen, 3-chloro-2-butenyl, 2-bromoallyl, benzyl, am Benzyl, methoxy or chlorine substituted on the ring; phenethyl, 3-phenylpropyl; 3-phenylpropyl substituted on the ring by chlorine, bromine or methoxy; furfuryl; 2-thenyl; C _{1 -C 5} -alkyl; C ₃ -C ₅ -alkenyl ; C ₃ -C ₅ alkynyl; cinnamyl; cinnamyl substituted with chlorine, bromine or methoxy on the ring; 3-phenyl-2-propynyl; C ₃ -C ₇ cycloalkyl; Q-Cg-cycloalkylmethyl; (methylcyclopropyl) methyl; (cis-2,3-Dimethylcyclopropyl) methyl; C ₆ -C8 cycloalkenylmethyl; C6 -Cg cycloalkadienylmethyl; (2,3-dimethylcycloprop-2-en-1-yl) methyl; exo-7-norcarylmethyl; ( cis -1 ^ -Dimethylendo-S-norcaren ^ -yO-methyl; (4-methylbicyclo [2.2.2] oct-1-yl) methyl; (4-methyl bicycio [2.2.2] oct-2-en-1-yl) methyl; (Bicyclo [2.2.2] hept-2-yl) methyl; (Bicyclo [2.2.2] hept-2-en-5-yl) methyl; 1-adamantylmethyl or 2-adamantylmethyl.

In the recently issued Belgian patent 8 45 368 (Derwent No. 00043Y) are S-phenyl-hexahydro-jö-carboline described, which optionally in the 2- and 4-positions by methyl or ethyl and substituted in the 3-position by alkyl having 1 to 3 carbon atoms, allyl or propargyl are. These compounds are useful as antidepressant agents.

In the recently published German Offenlegungsschrift 26 31 836 (Derwent No. 097738Y) structurally related octahydropyrido [4 ', 3': 2,3] indolo [l, 7-ab] [l] -benzazepine are described, which are described by the Formula given above can be derived in which Y * is an ethylene bridge between the two benzene rings, X * is a hydrogen atom and R ^{a is} a radical - CH ₂ CH ₂ COCH ₃ or - CH ₂ CH ₂ COC ₆ H ₅ . These compounds are also stated to be useful as analgesics and as tranquilizers.

In US Pat. No. 4,001,263 there are 5-aryl-1,2,3,4-tetrahydro-γ-carboline tranquilizers of the following formula described:

N-R ^b

in which X ^b and Z ^{b can be} a hydrogen atom or a fluorine atom, and the meanings of R ^{b can have} the meanings given above for R in the formula (I).

Surprisingly, it has now been found that the trans-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indoles according to the invention markedly superior tranquilizer activity compared to the corresponding 1,2,3,4-tetrahydro-γ-carbolines have, by orders of magnitude in the test for amphetamine antagonism, also that they have a much longer duration of action. Those according to the invention which are valuable as tranquilizers Compounds are the compounds of the following formula:

40

45

50

(CH ₂ ) "- M-

(D

55

60

and the pharmaceutically acceptable salts thereof, in which the hydrogen atoms bonded to the carbon atoms in the 4a and 9b positions are in a trans arrangement to one another and in which X, and Y ,, which can be the same or different, represent a hydrogen atom or a fluorine atom, η means the number 3, when M is the remainder

65

10 15th 20th 25th

40 45

O OH

Il Il

- C— or —CH-

is, or the number is 2 when M is the vinyl group and Z _{1 is} a hydrogen or fluorine atom or the methoxy group

The invention also relates to medicaments which are active as tranquilizers and a compound of the formula I 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 aforementioned prior art tranquilizers.

Particularly preferred tranquilizers according to the invention are the racemic mixtures of:

rido [4,3-b] indole,

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

pyrido [4,3-b] indole,

trans-5-phenyl-2- (4-hydroxy-4-phenylbutyl) -2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole,

tΓans-8-fluoro-5- (p-fluoφhenyl) -2- (4-hydΓoxy-4-phenylbutyl) -2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] -

indole,

trans-5-PhenyJ-2-P- (p-fluorobenzoy]) propyl] -2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole,

trans-8-fluoro-5- (p-fluorophenyl) -2- [3- (p-fluorobenzoyl) propyl] -2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3- b] -

indpl,

trans-8-fluoro-5- (p-fluorophenyI) -2- [4- (p-fluorophenyl) -3-butenyl] -2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4, 3-b] -

indole,

trans-S-Fluor-S-Cp-fluorophenylH-ß-ip-methoxyphenylH-butenyl ^^ a ^ b-hexahydro-lH-pyrido-

[4,3-b] indole,

h ^ i

[4,3-b] indole,

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

trans-S-Fluoro-S-io-fluorophenyO ^ - ^ - ip-fluorophenyOO-butenyl ^^^^ a ^^ b-hexahydro-1H-pyrido- [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 can be used:

NR ₂

BH ₃ / ether ₍

(VIII)

(IX)

50 55 60 65

(IX) (D (2)

ClCO ₂ C ₂ H ₅

KOH, C ₂ H _S OH / H ₂ O

NH

A preferred meaning for R ₂ is benzyl for economic reasons. However, R _{2 can} also have other meanings, and these can also be used in the scheme given above, as is known per se to the person skilled in the art. Examples of such alternative meanings for R ₂ are benzyl radicals substituted on the benzene ring, e.g. B. as substituents of one or more in the form of the methyl, methoxy, nitro or phenyl radical, and the benzhydryl radical.

The reduction of the tetrahydro-γ-carbolines of formula VIII to form the 4a, 9b-trans-hexahydro compounds of Formula IX is carried out in an ethereal solvent, usually tetrahydrofuran. To a To ensure complete reduction, a molar excess of borane / tetrahydrofuran is usually

complex (BH-THF) is used, and a 10C% 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 ° C, a temperature of about 0 ⁰ C until 6S ⁰ C preferred. Usually a solution of the starting material of the formula VIII in tetrahydrofuran is added to an ice-cold solution of BH ₃ · 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 S m hydrochloric acid. The acidified mixture is refluxed for 1 to 2 hours or more. The desired product can then be isolated, for example by evaporating any remaining ether solvent and part of the acid mixture, and the precipitated product collected by filtration and washed. In an alternative method of isolating product IX, the reaction mixture is filtered after refluxing, the filtrate is cooled and made alkaline by adding, for example, sodium hydroxide, potassium hydroxide or sodium carbonate. The basic mixture is mixed with a water-immiscible, organic solvent such. B. chloroform, methylene chloride or benzene, the extracts are evaporated and the residue is purified by column chromatography over silica gel and elution, e.g. B. using ethyl acetate or mixtures of hexane / ethyl acetate cleaned.

The reduction of the tetrahydro-γ-carbolines by BH ₃ · THF with subsequent acid treatment gives hexahydro-γ-carbolines in which the hydrogen atoms bonded to the carbon atoms in the 4a and 9b positions are in the trans arrangement, see, for example, the US - Patent 39 91 199.

The 2-benzyl 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 a suitable, reaction-inert, organic solvent with subsequent bender 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 dissolves without the formation of by-products. Examples of such 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 ten-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 ° C to 150 ⁰ C, typically up to the reflux temperature of the mixture, namely 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, for example sodium hydroxide or potassium hydroxide, is added in about a 10-fold to 30-fold molar excess, based on the amount of the starting material of the formula IX and the resulting mixture is refluxed, usually 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 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 FaI! From compounds of the formula IX in which both radicals X and Yi are hydrogen atoms and R _{2 is} the benzyl radical, the corresponding compound of the formula X can be obtained by catalytic debenzyling 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 ° C, and hydrogen pressures in the presence of a reaction of about 1.4 to 7 kg / cm ² 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 the formula X is precipitated by adding a nonsolvent such as ethyl ether, benzene or hexane Dry, partition of the residue between aqueous alkali, e.g. B. sodium hydroxide, and a solvent such as chloroform or ethyl ether can be isolated. The free base is then according to standard methods, e.g. B. the methods described above, isolated.

The free bases of the formula X can serve as precursor compounds for the new compounds of the formula VI, which is illustrated by the following reaction sequence, in which X, and Y ₁ , which can be identical or different, are each a hydrogen or fluorine atom, Z ₁ is Is hydrogen atom, fluorine atom or a p-methoxy radical and η is the number 3

O O

Il Il

C- (CHj) ₂ -COH

(xn) Y ₁ (xm)

NC- (CHj) ₂ -C- ^> -Z

OH

¹⁵ (ΧΠΙ) LiAlH ₄ .

20th

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. If the Acids of the formula XII are used in the acylation, are approximately equimolar amounts of these Acid and the compound of the formula X in the presence of an inert organic solvent and certain condensing agents known in the art for forming peptide bonds in combination

brought tact. Such agents include carbodiimides, e.g. B. dicyclohexylcarbodiimide and l-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride and alkoxyacetylenes, eg 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 ^° C. to 50 ^° C. with satisfactory results, a temperature of about 0 ^° C. to 30 ^° C. is preferably used. 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 evaporating the solvent. The product obtained is usually of sufficient purity for use in the next stage.
The intermediate of formula XIII is then reacted with lithium aluminum hydride.

The reduction is preferably carried out in the presence of an inert gas such as nitrogen or argon and under essentially anhydrous conditions. An approximately 2-fold to 10-fold molar excess of lithium aluminum hydride is suspended in an ethereal solvent, for example ethyl ether or tetrahydrofuran, and the mixture is preferably cooled ^{to a temperature of approximately 0} ° C. to 10 ^{° C.} The intermediate (XIII) is usually dissolved in the same solvent and the solution is added dropwise. The resulting mixture then reacts at room temperature for a period of about 0.5 to 4 hours to bring the reaction to practical completion. The excess lithium aluminum hydride is then decomposed, e.g. B. by careful addition of water, the resulting mixture is filtered and the filtrate is evaporated to dryness to obtain the desired product. This can then, if necessary, be cleaned by known standard methods.

The product of the formula VI is also isolated and purified according to the description given above, z. B. by column chromatography on silica gel.

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

55

60

65

(V)

ίο

BH ₃ / Ather H +

(VI)

N- (CHj) ₂ -CH = CH

wherein X ₁ , Y ₁ , Ζ |, have the meanings given above. The reaction with borane in an ether solvent, preferably tetrahydrofuran, and the subsequent treatment with acid is carried out under the conditions given above for the preparation of the 2-benzyl compounds of the formula IX. The products VI and VII are separated, for example, by column chromatography on silica gel.

The relative amounts of products VI and VII vary depending on the amount of acid, e.g. Hydrochloric acid, and the time of reflux after the reduction with BH ₃ · THF has taken place. Higher amounts of acid and longer reflux times favor the dehydrated product of the formula VI, while smaller amounts of acids and shorter reflux times favor the formation of the product VI.

The compounds of the formula VI can also serve as precursor compounds of the free bases of the formula X. The reaction is carried out using, for example, ethyl chloroformate, followed by an alkaline hydrolysis as previously described for the debenzylation of compounds of the formula IX, in which R _{2 is} benzyl, in order to obtain the free bases of the formula X, follows.

The oxidation of the compounds of Formula VI using reactants and conditions as known for the selective conversion of secondary alcohols to the corresponding ketones delivers the new products of the following formula:

wherein X ₁ , Y ₁ and Z _{1 have} the meanings given above. Examples of such oxidizing agents which can be used in this reaction are potassium permanganate, potassium dichromate and chromium trioxide, the preferred reagent being chromium trioxide in the presence of pyridine. In carrying out this reaction with the preferred reagent, the starting alcohol of formula VI is dissolved in a reaction-inert solvent, e.g. Dichloromethane, chloroform, or benzene, is added to a mixture containing up to a 10 fold molar excess of chromium trioxide and 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. By removing insoluble material by filtration, extracting the filtrate with a dilute aqueous alkali such as sodium hydroxide solution, drying the organic layer and evaporating to dryness. 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-phenyl-1,2,3,4-tetrahydro-y-carboline is obtained by Fiscner's indole synthesis using Ν, Ν-diphenylhydrazine and N-benzyl-4-piperidone. The mono- or di-fluoro-substituted starting tetrahydro-y-carbolines of the formula VIII, in which at least one of the radicals X ₁ or Y _{1 is} a fluorine atom and R _{2 is} the benzyl radical, are obtained from the corresponding compounds of the formula VIII in which R ₂ a hydrogen atom, by reaction with a benzyl halide such as benzyl bromide in equimolar amounts the necessary compounds of formula VIII, R ₂ = H, are as indicated in

20th

25th

30th

35

(XIV) 40

45

50

55

60

65

J ?; of US Patent 40 01 263 produced. The starting tetrahydro- ^ carboline VI are in the same pressure

^::: ■ magazine described.

; '- The other starting materials are either commercial products, their production is in the chemical

fr see literature exported! I described or they can be produced by methods known per se to the person skilled in the art.

' U 5 are placed. For example, phenylhydrazines are commercially available or they are obtained by reducing the phenyldiazonium salt according to the information provided by Wagner and Zook in "Synthetic Organic Chemistry",

ή · John Wiley & Sons, New York, N.Y., 1956, chapter 26. The l-substituted-4-piperidones are han-

Ινΐ the usual reagents or they are according to the method of McElvain and Rorig, J. Am. Chem. Soc, 70

^ j (1948), p. 1826. The required 3-benzoylpropionic acids and 4-benzoylbutyric acids are ent

^: Ίο either commercially available or they are by modification of the operation according to "Organic Syny thesis," Coll. Vol. 2, John Wiley & Sons, New York, NY, 1943, p. 81.

■; As described above, the basic compounds according to the invention can form acid addition salts.

The basic compounds are converted into their acid addition salts by contacting the base with a ·:. · Acid converted in either an aqueous or a non-aqueous medium. In a similar way it yields

15 the 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 in an equivalent amount of a metal cation, which forms an insoluble precipitate with the acid anion, the regression of the free base. The bases re-formed in this way can be the same or a different acid addition salt be converted back.

In utilizing the chemotherapeutic activity of the salts of the compounds according to the invention

It is of course preferred to use pharmaceutically acceptable salts. Although the insoluble

[ability in water, high toxicity, or lack of crystalline nature for any particular type of salt

Use as such in a given pharmaceutical application unsuitable or less suitable

I ₁ can make suitable, the water-insoluble or toxic salts can be incorporated into the corresponding pharmaceutical

1 25 table-acceptable bases can be converted by decomposition of the salt, as described above, or

alternatively, they can be added to any desired pharmaceutically acceptable acid addition salt be converted back.

Examples of acids that provide pharmaceutically acceptable anions are hydrochloric acid, Hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, sulphurous acid, phosphoric acid, 30 acetic acid, lactic acid, citric acid, tartaric acid, succinic acid, maleic acid and gluconic acid.

As described above, the compounds of the invention are easily used for a therapeutic compound, dung adapted as a tranquilizer in mammals.

The tranquilizers according to the invention are characterized by relief in the case of schizophrenic states

¹ in humans such as hallucinations, hostility, suspicion, emotional or social withdrawal,

j 35 anxiety, agitation and states of tension. Standard working methods for verification and comparison the tranquilizing activity of compounds in these series and for an excellent correlation with the effectiveness given in humans, the antagonism is induced by amphetamine Symptoms in the rat test as described by A. Weissman et al., J. Pharmacol. Exp. Ther., 151 (1966), p. 339 and von Quinton et al., Nature, 200: 178 (1963).

[■■■ 40 The γ-carbolines and the pharmaceutically acceptable salts thereof which are useful as tranquilizers,

: can be applied either as individual therapeutic agents or as mixtures of therapeutic agents

i 'be adorned. They can be applied on their own, but they are generally used together with

applied to a pharmaceutical carrier, taking into account the chosen route of administration and is selected according to standard pharmaceutical practice. For example, they can be taken orally in the form

45 of tablets or capsules containing such diluents as starch, lactose or certain types contained by clay, can be applied. They can be applied in the form of elixirs or oral suspensions where 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 in the form can be prepared from sterile, aqueous solutions. Such aqueous solutions should in a suitable manner,

50 may be buffered if necessary and they should contain other solutes such as salt or glucose to reduce the Adjust solutions isotechnically.

^: Although the use is directed to the treatment of mammals generally, it is preferred

Use in humans. As is readily apparent, the doctor can ultimately determine the dosage that ;.: is most suitable for a particular patient, this varies with age, weight and

£ .., 55 related to this particular patient, as well as the nature and extent of the symptoms and the pharmacodynamic Mix the properties of the particular agent to be applied. Generally be at the beginning

p only small doses applied, gradually increasing the dose until the optimal level

[f is determined. It is often found that when the agent is administered orally, larger amounts of active ingredient

i? substance are required to achieve the same effect as a smaller amount in the case of the parent

ff 60 ralen application is achieved.

i | Taking into account the factors described above, it is believed that the daily dosage of the

p | Compounds of the invention in humans approximately 0.5 to 100 mg with a preferred range

-I from 1 to 25 mg results in an effective tranquilizer effect In those individuals in whom the invention

If compounds have a longer effect, the dose can be 5 to 125 mg per week, administered in one

»I 65 or two divided single doses. These values are for explanatory purposes only and are self-evident Of course, in individual cases, higher or lower dose ranges can be advantageous.

j.: The preparation of the compounds according to the invention is explained in more detail using the following examples.

example 1

(Starting compound A) s

A solution of 23.9 g = 0.071 mol of 2-benzyl-5-phenyl was added to a stirred at 0 ^° C. solution of 0.140 mol of borane in 150 ml of tetrahydrofuran in a three-necked flask equipped with a magnetic stirrer, thermometer, condenser and addition funnel and kept under a nitrogen atmosphere -l, 2,3,4-tetrahydropyrido [4,3-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 in vacuo to give a white solid mass which was suspended in 40 ml of dry tetrahydrofuran and initially slowly heated 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 some 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 trans isomer; F. 256-260 ⁰ C.

Evaporation of the mother liquor gave a further 7.2 g of the product, which contained a small amount of the cis isomer were contaminated.

Example 2

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

(Starting compound B)

A suspension of 4.15 g of dl-trans-2-benzyl-5-phenyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole hydrochloride in 150 ml of absolute ethanol was at 3.5 kgf / cm ² and 60-70 ⁰ C using 1.0 g of 10% Pd / C catalyst over a period of 2 hours hydrogenated. The catalyst was removed by filtration and sufficient ethyl ether was added to the filtrate to precipitate the hydrochloride of the desired product; Yield = 2.76 g (87%); M.p. 235-237 ° C.

The hydrochloride salt was dissolved in the free base by partitioning between ether and dilute sodium hydroxide converted The ether layer was dried over sodium sulfate and evaporated, whereby the the title compound was obtained in 97% yield; M.p. 74-76 ° C.

Example 3

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

y ^^^
hexahydro-1H-pyrido [4,3-b] indole hydrochloride

In a equipped with a magnetic stirrer and dropping funnel and kept under a nitrogen atmosphere To reaction vessels of 1000 ml, 177 ml of 0.94 M borane tetrahydrofuran solution were added. The solution was cooled in an ice bath and the cold solution was added to oine over a period of 30 minutes Solution of 25 g = 0.0555 mol of 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 at ambient temperature stirred for 20 minutes, then it was refluxed for 2 hours. The reaction mixture was cooled and concentrated in vacuo to give a liquid residue. to to this residue was added a mixture of 50 ml each of acetic acid and 5N hydrochloric acid, whereupon a vigorous evolution of gas occurred.

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 dried over magnesium sulfate and evaporated to dryness in vacuo to give 25 g of a yellow, foamy solid. 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 TLC (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.

The only the more slowly migrating 8-fluoro-5- (p-fluorophenyl) -2- [4-hydroxy-4- (p-fluorophenyl) -butyi]] - 2,3,4,4a _T 5,9b-hexahydro- Fractions containing 1H-pyrido- {4,3-b] indole were concentrated, taken up in ethyl ether and converted to the hydrochloride salt by the addition of anhydrous hydrogen chloride to give 10.8 g of this product, mp 241-245 ° C.

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

Example 3A

When the procedure of Example 3 is repeated, however, using 8-fluoro-5- (o-fluorophenyl) -2- [4-hydroxy-4- (p-fluorophenyl) butyl] -2 ^, 4.5 -tetrahydropyrido [4,3-b] indole As a starting material, the more rapidly migrating component was found in silica gel chromatography to be trans-8-fluoro-5- (o-fluorophenyl) -2- [4- (p-fluorophenyl) -3-butenyl] -2,3,4,4a, 5 , 9b-hexanhydro-1H-pyrido [4,3-b] indole obtained with a mp of 141-142 ° C. The slower migrating component was identified as trans-8-fluoro-5- (o-fluorophenyl) -2-14-hydroxy-4- (p-fluGrphenyl) -butyl] -2,3,4,4a, 5,9b-hexahydro -lH-pyrido [4,3-b] indole identified with m.p. 195-197 ° 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 in the respective Cases received and separated.

N- (CH ₂ ) J-CH 1 f> - Z ₁ OH

(D

(V)

N- (CH ₂ Jj- CH-f OH

(D

(VI)

+ Xl

(VII)

10

Compound of formula

F CC) *)

VII (example 3A)

H F

F H

p-fluoro H

p-fluor

H p-fluorine

o-fiuor

H p-fluorine

p-methoxy

p-fluorine p-fluorine

p-fluor

220-223
239-245

45-48.5 (free base)
226-229

199-201
208-210

195-197

141-142 (free base)

*) Hydrochloride, unless otherwise stated.

Example 5

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

A) To a solution of 5.6 g = 12.4 mmol of dHrans-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 5.3 ml = 55.7 mmol of ethyl chloroformate given. The resulting mixture was refluxed overnight and then evaporated to dryness, a gummy product was obtained as residue. About this rubbery product 200 ml of a 9: 1 volume mixture of ethanol / water were added. After the rubbery Dissolved product, 15 g of potassium hydroxide was added and the resulting mixture was added 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 dissolved in ethyl acetate added and sent through a silica gel column, first with ethyl acetate for removal was eluted by by-products and then the desired product with a 1: 1 volume mixture Ethyl acetate / methanol was eluted. The fractions containing the compound named in the heading were combined and evaporated to dryness to give 1.6 g (43%) of a yellow gummy product which crystallized on standing; 115-117 ° C.

B) Alternatively, dl-trans -2-benzyl-8-fluoro-5- (p-fluorophenyl) -2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole hydrochloride in the presence of excess ethyl chloroformate or the corresponding methyl, isopropyl or refluxing n-butyl chloroformate ester and then following the procedure described above hydrolyzed and worked up to obtain the title compound.

C) 780 g of a carbon catalyst with 5% palladium (50% water content) were placed in an enamelled pressure vessel, as well as 1167 ml of water, 1556.5 g (3.77 mol) of dl-trans-2-benzyl-8-fluoro-5 - (p-riuophenyl) -2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole hydrochloride and 86.11 methanol. The vessel was flushed with nitrogen, then pressurized ^{to 3.5 kg / cm 2 with hydrogen and finally with hydrogen.} The mixture was then hydrogenated at 25 ° -41 ° C. until there was no more uptake of hydrogen (about 2 hours). The container was degassed, purged with nitrogen and the reaction mixture was nitrated to remove the catalyst. After washing with methanol, the filtrate and washing liquids were concentrated under reduced pressure. 28 l of methylene chloride and 87 l of water containing 852 g of NaOH were added to the residue. The resulting mixture was stirred for 10 minutes (pH = 12) and the layers were then separated. The aqueous layer was extracted with a second portion of 28 liters of methylene chloride, the organic layers were combined and washed with 26.5 liters of water. The organic extracts were dried over anhydrous magnesium sulfate and concentrated with the addition of 95 l of hexane in order to displace the methylene chloride. The resulting slurry was cooled to 8 ° C, filtered, washed with hexane and dried to give 1446 g (67%) of the desired product with mp = 115-118 ° C.

Analysis for Ci ₇ Hi ₆ F ₂ N ₂ :

Calcd .: C = 71.31; H = 5.63; N = 9.79; F = 13.27; found: C = 71.25; H = 5.50; N = 9.76; F = 13.28.

Mass spectrum (m / e): 286 (100, m ⁺ ), 257 (50), 256 (72), 243 (61), 242 (57), 148 (32), 135 (36), 57 (79).

Example 6

Using the appropriate starting materials in each case and using the Working procedures of Examples 5A or 5B, the following products were obtained in a comparable manner:

11th

ippyO ^ A ^{F =} 235-238 ° C,

dl-trans-8-fluoro-5-phenyl-2 ^, 4,4a ^^ b-hexahydro-1H-pyrido [4,3-b3indole-hydrochloride, F = 244-246 ° C,

Cpyö ^^^
d! -trans-5- (o-fluorophenyl) -8-fluoro-2,3,4,4a _J 5,9b-hexahydro-1H-pyrido [4,3-b] indole, dl-trans-5- ( m-fluorophenyl) -8-fluoro-2,3,4,4a, 5 _> 9b-hexahydro-1 H -pyrido [4,3-b] indole, dl-trans-5- (m-fluorophenyl) -2,3 , 4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indoI.

Example 7
ίο dl-trans-2- (4-hydroxy-4-phenylbutyl) -5-phenyl-2,3,4,4a, 5,9b-hexahydro-1H-pyridote 4,3-b] indole hydrochloride

Mg A) To the suspension obtained from the mixing together 865 mg = 4.20 mmol dicyclohexylcarbodiimide and 748 to 4.20 mmol of 3-benzoylpropionic acid in 30 ml Dichlonnethan at 0 ⁰ C, was added 1.0 g = 4.0 mmol dl -trans-5-phenyl-2,3,4,4a ^, 9b-hexahydro-1H-pyrido [4,3-b] indole in 10 ml of the same solvent was added. The resulting mixture was stirred for a period of 2 hours and warmed to room temperature. After cooling again to 0 ^° C., the reaction mixture was filtered, washed with dichloromethane, and the filtrates were evaporated, leaving a residue of dl-trans-2 - [( 3-BenzoyI) propionyl] -5-phenyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,34 *] indole, which was used in the next step without further purification.

B) The residue obtained from the previous step was dissolved in 50 ml of tetrahydrofuran and taken under 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 under Stirred at reflux for 5 to 10 minutes, then cooled. There was 17 g of anhydrous, powdered Sodium sulfate was added, followed by 0.5 ml of water. The resulting mixture was at room temperature stirred for 30 minutes, filtered and the filtrates 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 eluted to give the free base of the title compound after evaporation of the solvent. The free base was converted into the hydrochloride salt by dissolving in ether, Addition of a saturated solution of anhydrous hydrogen chloride in ether until the formation of a precipitate is complete, Filter and dry converted to give 1.04 g of m.p. 222-224 ° C.

IR spectrum (KBr) *: 2.97, 3.43, 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) l _max 245 (ε = 0.653 X ΙΟ ⁴ ), 270 (c = 0.914 X 10 ")

Example 8

Using the appropriate starting material in each case, taking this from those in the examples 2 and 5, and the corresponding 3-benzoylpropionic acid the following dl-trans compounds were prepared by following the procedure of Example 7. The products were isolated as hydrochloride salts unless the exception is noted.

NCH ₂ CH ₂ CH ₂ CH-OH

Xl

F. F. H H H H F. F.

F. ⁰ C

yield

H 220-223 18

F 239-245 39

CH ₃ O amorphous solid (a) 54

CH ₃ O 45-48.5 (b) 31

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

IR spectrum (KBr), _μ : 2.98, 3.42, 4.07 (broad), 6.20, 6.26, 6.70, 6.88, 8.04, 8.54, 9, 77, 12.05

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

Example 9

dl-trans -5-phenyl-2- [3- (p -fluorobenzoyl) propyl] -3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole hydrochloride

0.828 ml = 8.0 mg = 10.3 mmol of dry pyridine and 10 ml of dichloromethane were placed in a 25 ml reaction vessel equipped with a magnetic stirrer and kept under a nitrogen atmosphere. 517 mg = 5.17 mmol of chromium trioxide were added to the solution, and the dark red suspension obtained was stirred for 15 minutes at room temperature. A solution of 359 mg = 0.862 mmol dl-trans-5-PnenyI-2- [4-hydroxy-4- (p-fluorophenyl) -butyl] -2,3,4,4a, 5,9b-hexahydro-1H- Pyrido [4,3-b] indole in the form of the free base in 5 ml of dichloromethane were added all at once. The reaction mixture quickly turned to a brown suspension. 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 extracted with 20 ml of 10% sodium hydroxide solution. The organic layer was _{dried over MgSO 4} and evaporated to dryness in vacuo to give a gummy product. This gummy product was purified by column chromatography on silica gel while 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, 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. A colorless solid formed which was collected by filtration and dried to give 20 mg of the named compound having a mp of 244-246.5 ° C.

Example 10

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

To a 100 ml flask containing 20 ml of dichloromethane and 1.76 nl = 21.9 mmol of pyridine was added 1.09 g of chromium trioxide and the resulting dark suspension was stirred at ambient temperature for 15 minutes. Then 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-pyrido [4,3-b] indole in the form of the free base (obtained from the hydrochloride salt by making an aqueous solution alkaline with sodium hydroxide, extraction with dichloromethane and evaporation of the extracts to dryness ) added in 10 ml dichloromethane. The resulting red-brown suspension was stirred at ambient temperature for 1 hour and worked up by the methods used in Example 9 of operation, wherein 25 mg of the desired product with F. 260-263 ⁰ C were obtained.

Example 11

dl-trans-S-Fluor-S-ip-fluorophenylH - ^ - hydrocy ^ -ip-fluorophenylJ-butylj ^ vMa ^ bhexahydro-1 H-pyrido [4,3-b] indole acetate

5 g dl-trans-S-fluoro-ip-fluorophenyO ^ - ^ - hydroxy ^ -ip-fluorophenylJ-butyl ^^^^ a.S ^ b-hexahydro-1H-pyrido [4,3-b] indoi hydrochloride in 75 ml of water were mixed with 3 ml of water containing 1.0 g of sodium hydroxide, treated, and the released compound in the form of the free base was extracted into 150 ml of diethyl ether. the The ether layer was separated off, dried over magnesium sulfate and treated with 1 ml of glacial acetic acid. The organic one Solvent and the excess of acetic acid were removed under reduced pressure, and the The residue was triturated with hexane and filtered

Similarly, other acid addition salts, particularly those that are pharmaceutically acceptable are to be produced.

Example 12
Trials and results

The effects of the compounds of 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. Grappes of five rats were placed in a covered plastic cage approximately 26 cm x 42 cm x 16 cm. After a brief period of acclimatization in the cage, the rats in each group were treated subcutaneously with the test compound. They were then treated 1, 2 and 24 hours later with d-Amphetamine sulfate at a dose of 5 mg / kg intrapcritoneally (ip) treated. 1 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, which was required for the antagonism or the blocking of the characteristic amphetamine behavior of the cage movement of 50% of the examined rats (ED _5n ). The chosen grading time coincides with the peak effect of anphetamine, which is 60 to 80 minutes after treatment with this agent.

28 22 465 H Yi Λ H 14th ED ₅₀ (mg / kg) 2h 24 hours II
ν / C ₂ H ₅ lh 0.032-0.1 0.1-0.32 H H Y, 0.032-0.1 0.1-0.32 0.1-0.32 Using the procedure previously described, the following 4a, 9b trans compounds were revealed
examined their ability to block the behavioral effects of amphetamines, the results being as
ED _{5 (} | values are given in mg / kg at the times given: F. H R. 0.1-0.32 0.1-0.32 -1.0 F. H C ₆ H ₅ CH- (CH ₂ ), -
ι 0.1-0.32 I.
OH 0.1-0.32 -0.32 p <b> H P-FC ₆ H ₄ CH- (CH ₂ ) J-
ι -0.32 F. I.
OH 0.1-0.32 <0.32 F. p-fluor P-CH ₃ OC ₆ H ₄ CH- (CH ₂ ) J- 0.1-0.32 Table I. F. OH 0.032-0.1 0.032-0.1 Xi p-fluor P-FC ₆ H ₄ C- (CH ₂ ) J-
Il 0.032-0.2 F. Il
O <0.32 <0.32 H p-fluor C ₆ H ₅ CH- (CH ₂ ) J- 0.32-1.0 3.2-10 3.2-10 _H .ci o-fluorine I.
OH 10 <1 <1 _H (a) H ' ^cl p-fluor P-FC ₆ H ₄ CH- (CH ₂ ) J- 1-3.2 <0, l <0.32 • p-fluor I.
OH 0.1-0.32 p — FC ₆ H ₄ CH = CH- (CHj) ₂ - <1.0 <l, 0 p-fluor p — FC ₆ H ₄ CH = CH- (CHz) ₂ - <l, 0 P-CHjOC ₆ H ₄ CH = CH- (CHz) ₂ - > 3.2 > 32 H P-CH ₃ OC ₆ H ₄ CH- (CHz) ₂ - 3.2-32 > 3.2 NT " ¹¹ H OH -1.0 P-FC ₆ H ₄ C- (CHz) ₃ -
H Il
O 5 10 15th 20th 25th 30th 35 40 45 50 55 60 65

continuation

X ₁ Y,

ED ₅₀ (mg / kg) 2 h -32 24 hours lh 3.2 -10 > 3.2 -10 3.2 -0.32 > 10 3.2-10 0.1 0 0.32-1.0 0.1-0.32 > 1 > 32 0.32-1.0

H ^lc) HC ₆ H ₅ CH ₂ -

H ^lc) HC ₆ H ₅ (CH ₂ ) ₃ -

8-fluoro-5- (p-fluoro-phenyl) -2- [4-hydroxy-4- (p-fluoro-phenyl) -butyl] -l, 2,3,4-tetrahydro-y-carboline ^(c)

Navane ^(f) , po

15 Notes:

") The corresponding 4a, 9b-cis analogue had an ED 50 value of ~ 56 mg / kg at 1 h.

^b ) ED ₅₀ at 48 h <0.32; 72 h <0.32.

^c ) U.S. Patent 3,991,199.

^ü ) Not investigated. ^20th

^c ) U.S. Patent 40 01 263.

') cis ^ -P ^ -Methyl-1-piperazinyD-propylidenl ^ -dimethylsulfonamidoHhioxanthene, U.S. Patent 33 10 553.

The LD50 values for the connection with X | = F, Y | = F and Zi = Fund M = CHOH were p in male mice. O. 52-114 mg / kg, in female mice p. o. 244 mg / kg and in male mice i. p. 57-97 mg / kg. For male advice- 25 The corresponding LD5 (| values p. 0.52-89 mg / kg and 57 mg / kg i.p., for female rats p. o. 89 mg / kg the same connection with M = C = O could be found in mice at i. p. and oral administration do not observe any deaths up to 100 mg / kg! will.

Comparative tests 30

Following the procedure of Example 12, which is essentially that of Example 24 of US Pat. No. 4,001,263 corresponds to the test procedure described, comparative tests were carried out.

In the following Table II the results of these comparative tests are given with regard to the ED ₅₀ values for a number of compounds, these compounds differing only in terms of two hydrogen atoms. These results are listed in pairs, the results "(a)" referring to the tetrahydrocarboline compounds of the following formula (II) in US Pat. No. 4,001,263, while the values labeled "(b)" refer to the corresponding trans-hexahydro compounds of the following formula (I) according to the invention.

ti

so

α -ε

UJ -

JO

α α

I.

° ι

rs'

ro CN O ^

ro 'θ'

Ξ ι

^Μ

CO

CNO ro O

α α

ο ο

α α

α α

α α

α α

α ο.

rs

O (1

—Ό 'I I

ro 'θ'

I I I

rs
ro. cs ° (N
Ή **} O'
I. , 0-3,
, 032- ro 'O
II O' - O ■ - <'©'

O O

¹ V Λ SV

o H .;

ro 'ι Ο I rs I ι ¹ ro CS I

o 'o' o 'o'

O °,

AV

S V

O,

O '(N I <- ·

IS co ', I ₁ IO

- ο ι m es ι- ¹

θ 'θ' -ι θ 'ro' V

ΓΟ ■ —I i — 1

o'o'V

"ce

'S ¹ S

XU-O X
U

X O

XX U-O

U.

-3

U U = O

U.

α.

χ ac

U-O U

U-

rs ro ^ ro'o ' AV

CS

(N ro ro'o ' AV

CS CS C \

ro'o ' AV

CS O ^

ro 'θ'

, 32 O, O' CN © ' (N O
I. co '
I. O I.
CN I.
T— ( ro '
I. V ro ' I.
CS
ro O V ro O ο A. O ~ £ O' O' , -T O

O _-1 2- (N (N (N rs τ-Η
I. I. ro_ CS ro,
m'o ro ' ro
d O rs CS I. ι ι A. I. I. ro ro ' T-H O ¹ ^ -— * rs O O Ö co ' O'

-O

ac χ

U-O X UO

ac

U-

Q.

X U

XX UO

rc

U-

The values given in Table H clearly show that the compounds according to the invention are compared to corresponding compounds of US-PS 40 01 263 are surprisingly more effective, the differences up to 2 orders of magnitude or that in many cases they have a longer duration of action.

In further comparative tests, the commercial products Haioperidol and Chlorpromazine - HCl are used dl-lrans-8-fluoro-5- (p-fluorophenyl) -2- [4-pf] uorophenyl) -4-hydroxybutyl] -2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4 , 3-b] indole hydrochloride compared.

The compounds were tested for their ability to block the effects of amphetamine taking The procedure described in Example 12 is used as a basis.

Compound A is sharkoperidol, a commercially available tranquilizer with the formula

OH

4 — FC ₆ H ₄ CO (C ΗΛ—

Compound B is chlorpromazine hydrochloride, a commercially available tranquilizer with the formula
CH ₂ CH ₂ CH ₂ N (CHj) ₂
N

γ-γα

HCl

Compound C is a compound of the invention having the formula

NCH ₂ CH ₂ CHCH-OH

Γ 11 HCl ED50 (mg / kg) zi i the times mentioned ED ₅₀ (mg / kg) at subcutaneous V 1 sltl. 5h I.
F. 0.2
(0.13-0.32) 0.72
(0.45-1.15) 24 hours 48 hours Table III 5.3
(4.4-6.4) 8.5
7.3-9.9) > 32 0.41
(0.3-0.6) 0.03
(0.027-0.04) > 32 0.03
(0.027-0.04) 0.27
(0.2-0.5) Blockade of the amphetamine stereotype in rats
delivery (95% confidence limits in brackets) link A. B. C.

All three compounds A, B and C are potent inhibitors of the amphetamine stereotype. However that is Compound C is already effective at a much lower dosage and has a much longer duration sustained activity than compounds A and B.

15 20 25 30 35 40 45 50 55 60 65

Claims (1)

Patent claims: 1,2-substituted-trans-5-phenyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole derivatives of the general Formula I. ^ N- (CH ₂ ), - Μ— <> —Z, (I) wherein the hydrogen atoms bonded to the carbon atoms in the 4a and 9b positions are in the trans arrangement to one another and X ₁ and Y ₁ , which may be the same or different, are a hydrogen atom or fluorine atom, η denotes the number 3 when M is the remainder