CS207613B2 - Method of making the trans-5aryl-2,3,4,4a,5,9b-hexahydro-1h-pyrido 4,3-b indoles - Google Patents

Description

(54) A method for producing trans-5-aryl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indoles

The present invention relates to certain trans-2-substituted-5-aryl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-bindole derivatives, a process for their preparation, their use as tranquilizing agents and pharmaceutical compositions containing the compounds as active ingredients.

After the introduction of reserpine and chlorpromazine into * psychotherapy medicine in the early 1950s, a great deal of effort was devoted to the search and development of other tranquilizing agents with improved biological properties. Some of these agents are γ-carboline derivatives, also known in the art as pyrido [o] [4,3-b] indole derivatives.

U.S. Patent 3,687,961 discloses 8-fluoro-2- [3- (4-fluorophenylanilino) propyl] -1,2,3,4-tetrahydro-γ-carbonyl as a useful tranquilizing agent for warm-blooded animals. U.S. Pat. No. 3,755,584 discloses structurally related compounds having a fluorine atom at the 6 or 8 position and a characteristic p-substituted phenylalkyl radical at the 2-position, which have been found to have similar activity.

U.S. Pat. No. 3,983,239 discloses hexahydro-γ-carbolines of the general formula

in which,

R ^{1 * * * V} is methyl or ethyl and

R ² is hydrogen, methyl or ethyl.

In this work there is no mention of the stereochemical arrangement of the hydrogen atoms at the 4a and 9b positions, but it could be expected that their relative arrangement would be cis due to the formation of the hexahydro-χ-carboline * nucleus from the starting 1,2,3,4-tetrahydio of? -carboline by catalytic hydrogenation in the presence of platinum, which is a known method of introducing cis-hydrogen hydrogen atoms to a double bond between carbon atoms. The compounds protected by this patent are neuroleptic agents which are said to be useful in the treatment of schizophrenia.

U.S. Pat. No. 3,991,199 discloses hexahydropyrimido [4,3-b] indoles useful as analgesics and sedatives, some of which are of interest as tranquilizing agents, some of them as muscle relaxants, and many of them exhibit hypotensive activity. Said substances are compounds of the general formula

in which the hydrogen atoms attached to carbon atoms in the positions 4a and 9b are trans to each other, and wherein in the event that ^Y is hydrogen ^and X represents hydrogen, chlorine, bromine, methyl, tert-butyl or methoxy, and in the event that ^Y represents trlfluormethylovou group, X represents ^a hydrogen atom, and R ^a is hydrogen, 3-chloro-2-butenyl, 2-bromallylovou, benzyl, benzyl substituted in the ring by a methyl group , methoxy or chloro, phenethyl, 3-phenylpropyl, 3-phenylpropyl substituted in the ring by chlorine, bromine or methoxy, furfuryl, 2-thenyl, alkyl of 1 to carbon atoms, alkenyl of 3 up to 5 carbon atoms, (C 3 -C 5) alkynyl, cinnamyl, ring substituted cinnamyl, bromo or methoxy, 3-phenyl-2-propynyl, cycloalkyl of 3 to 7 carbon atoms, cycloalkylmethyl of 4 to 8 carbon atoms, (methylcyclopropyl) -methyl, (cis-2,3-dimethylcyclopropyl) methyl, cycloalkenylmethyl (C až-C 8) group, (C až-C cyk) cycloalkadlenylmethyl, (2,3-dimethylcycloprop-2-en-1-yl) methyl, (exo-7-norarylmethyl), (cis-1,6-dimethylenedio-) 3-norocaren-7-yl] methyl, (4-methylbicyclo [2.2.2] oct-1-yl) methyl, (4-methylbicyclo [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 A 2-adamantylmethyl group, and pharmaceutically acceptable salts thereof.

More recently, Belgian Patent Specification No. 845,368 (Derwent No. 0043Y) discloses

5-phenyl-hexahydro-β-carbolines, optionally substituted at the 2- and 4-positions with methyl or ethyl, and at the 3-position with C 1 -C 3 alkyl, allyl or propargyl. These compounds are useful as antidepressants.

Recently, DOS No. 2,631,836 (Derwent No. 09738Y) describes structurally related octahydropyrido [4 ', 3': 2,3] indolo [1,7-ab] [1] benzazepines, which can be represented by the above general formula, wherein Y ^a represents an ethylene bridge between two benzene rings, X ^a represents a hydrogen atom and R ^a represents a group -CH 2 CH 2 COCH 3 or · —CH 2 CH 2 COC 6 H 5.

These agents are said to be useful as analgesics and tranquilizers.

U.S. Pat. No. 4,001,263 discloses transquilizing 5-aryl-1,2,3,4-tetrahydro-1H-carbolines of the general formula

in which X ^b and Z ^b are hydrogen or fluorine, and R ^b has the same meaning as the above R in formula I.

It has now been unexpectedly found that the trans-2,3,4,4a, 5,9-hexahydro-1H-pyrido [4,3-b] indoles of the invention have a significantly better tranquilizing activity compared to the corresponding 1,2,3, 4-tetrahydro-γ-carbolines.

Valuable tranquilizing agents which can be prepared by the process of the invention are the enantiomeric and racemic compounds of formula II

wherein the hydrogen atoms attached to the carbon atoms at positions 4 and 9b are trans to each other, each of the symbols

X and Y, which may be the same or different, are hydrogen or fluorine, n is 3 or 4, and Z is hydrogen, fluorine or methoxy, and pharmaceutically acceptable salts thereof.

The invention also provides methods for treating the manifestation of schizophrenia in a mammal, comprising administering to a mammal in need of such treatment an orally or parenterally transiently effective amount of a compound of Formula II.

The invention further encompasses tranquilizing pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a compound of Formula II.

The compounds of the invention exhibit a marked and unexpectedly higher tranquilizing effect compared to the aforementioned prior art tranquilizing agents.

Particularly preferred tranquilizing agents of the invention are the enantiomers and racemic mixtures of the compounds listed below:

trans-8-fluoro-5- (p-fluorophenyl) -2- [4-hydroxy-4- (pfluorophenyl) butyl] -2,3,4,4a, 5,9b-hexahydro-1H-pyrido 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- [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, trans-8-fluoro-5- (fluorophenyl) -2- (4-hydroxy-4-phenylbutyl) -2,3,4, 4a, 5,9b-Hexahydro-1H-pyrido [4,3-b] indole, trans-8-fluoro-5- (of fluorophenyl) -2- [4-hydroxy-4- (p-fluorophenyl) butyl] -2 3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole and trans-5-phenyl-2- [4-hydroxy-4- (fluoro-phenyl) butyl] -2, 3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole.

In accordance with the process of the invention, the compounds of formula (I) above are prepared from the free base starting materials of formula (V).

wherein X and Y are as defined above, according to the following reaction scheme:

^Live * gr ^c

O

- (CHJ ^ COH_ * (IV))

Y (u)

The preparation of the free base bases of formula (V) is described in our related Czechoslovak patents 207,612, 207,614, 207,615.

For the acylation of compounds of formula V to give intermediates of formula III, acids of formula IV or chlorides or bromides of the corresponding acids can be used. When the acids of formula (IV) are used for acylation, roughly equimolar amounts of the aforementioned acid -a of the compound of formula (V) are contacted in the presence of an inert organic solvent and a condensing agent known to be used to form peptide bonds. These include carbodiimides such as dicyclohexylcarbodiimide and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, and alkoxyacetylenes such as methoxyacetylene and ethoxyacetylene. tetrahydrofuran, ethyl ether and benzene Although the reaction can be carried out satisfactorily at a temperature of about -10 ° C to 50 ° C, the reaction is preferably carried out at a temperature of about 0 ° C to 30 ° C. The product of formula III is isolated, for example, by filtering off the insolubles and evaporating off the solvent, and the product obtained is usually sufficiently pure for use in the next reaction step.

The intermediate of formula III is then reacted with lithium aluminum hydride. The resulting product of formula (II) is isolated and purified, for example, by silica gel column chromatography.

As mentioned above, the basic compounds of the invention may form acid addition salts. Said basic compounds are converted into their acid addition salts by reacting the base with an acid in either an aqueous or non-aqueous medium. Similarly, by reacting the acid addition salts with an equivalent amount of an aqueous base solution such as an alkali metal hydroxide, an alkali metal carbonate or an alkali metal bicarbonate, or an equivalent amount of a metal cation forming an insoluble precipitate, the corresponding free base is recovered. The recovered bases can then be converted to the same or other acid addition salts.

Obviously, pharmaceutically acceptable salts are preferably used in the chemotherapeutic action of the salts of the compounds of the invention. Although water insolubility, high toxicity or non-crystalline character may make certain salts unsuitable or less desirable for a given pharmaceutical application, the water-insoluble or toxic salts may be converted to the corresponding pharmaceutically acceptable bases by the above decomposition, salt, or alternatively converted to any desired pharmaceutically acceptable acid addition salts.

Examples of acids providing pharmaceutically acceptable anions include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, sulfuric acid, phosphoric acid, acetic acid, lactic acid, citric acid, tartaric acid, succinic acid, and maleic acid. by gluco-n.

As mentioned above, the compounds of the invention may be used therapeutically in mammals as tranquilizing agents.

The efficacy of the tranquilizing agents of the invention is characterized by releasing such schizophrenic manifestations in humans as hallucinations, hostile behavior, suspicion, emotional or social alienation, anxiety, agitation, and tension. Standard procedures for detecting and comparing transient efficacy of the compounds of this group, which achieve excellent correlation of the observed results with human efficacy, consist of antagonizing amphetamine-induced symptoms in rats, as described by A. Weissman et al. in J. Pharmacol. Exp. Ther., 151, 339 (1966) and Quint-on et al in Nature, 200, 178 (1963).

χ-Carbolines and their pharmaceutically acceptable salts useful as tranquilizing agents can be administered either as individual therapeutic agents or as mixtures of therapeutic agents. The compounds may be administered alone, but are generally administered together with a pharmaceutical carrier selected taking into account the intended route of administration and standard pharmaceutical practice. For example, the compounds may be administered orally in the form of tablets or capsules containing, for example, starch, milk sugar, certain types of clay, and the like as carriers. Furthermore, the compounds may be administered as elixirs or suspensions for oral administration in which the active ingredients are bleaching agents and suspending agents. The compounds of the invention may further be injected parenterally, for example in the form of sterile aqueous solutions. These aqueous solutions may be suitably buffered if necessary and are intended to contain other insoluble substances, such as sodium chloride or glucose, for isotonization.

While the compounds of the invention may be used to treat mammals in general, they are preferably used in human medicine. The precise dosage best suited to which patient, which will vary depending on the patient's age, weight and response to the preparation, as well as the nature and extent of the symptoms and the pharmacodynamic properties of the substance administered, will, of course, be ultimately determined by the attending physician. In general, small dosages are administered initially and gradually increased to the optimum level.

Often, when administered orally, greater amounts of the active ingredient are required than parenteral to achieve the same effects.

In view of all the above-mentioned circumstances, it is believed that transquilizing effects in humans are achieved with daily dosages of the compounds of the invention of about 0.5 to 100 mg, preferably 1 to 25 mg. In those individual cases where the compounds of the invention have a protracted effect, a weekly dose may be administered in a single dose or in two divided doses, or a 5 to 125 mg weekly dose may be administered in two divided doses. These values are merely illustrative and, of course, there may be individual cases requiring higher or lower dosages.

All compounds of the invention contain at least two asymmetric centers resulting in the reduction of the double bond at positions 4a, 9b to a saturated trans-system. The invention includes both racemates and individual enantiomers. Further, when the substituent at the 2-position contains a moiety that may exist in stereoisomeric forms, the diastereoisomeric opoates from the diastereoisomers will also be present.

The invention is illustrated by the following non-limiting examples. Individual abbreviations for signals in NMR spectra have the following meanings:

s = singlet d = doublet t = triplet q = quartet m = multiplet

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

A. To a suspension of 865 mg (4.20 mmol) of dicyclohexylcarbodiimide and 748 mg (4.20 mmol) of 3-benzoylpropionic acid in 30 ml of dichloromethane at 0 ° C was added 1.0 g (4.0 mmol) of dl. trans-5-phenyl-2,3,4,4a, 5,9b-hexahydro-1H-pyridd [4,3-b] indole in 10 mL of the same solvent. The resulting mixture was stirred for 2 hours while allowing to warm to room temperature. After cooling to 0 ° C again, the reaction mixture was filtered, the filter residue was washed with dichloromethane and the filtrate was evaporated to give dl-trans-2 - [(3-benzoyl) propionyl] -5-phenyl-2,3 as a residue. 4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole, which was used in the next step without purification.

B. The residue obtained above was dissolved in 50 ml of tetrahydrofuran and the solution was heated to boiling and a filtered solution of lithium aluminum hydride in q of the same solvent was added until gas evolution (molar excess) was complete. The mixture was refluxed under stirring for 5-10 minutes, then cooled, firstly 17 g of anhydrous sodium sulphate powder was added, followed by ¹ 0.5 ml of water. The mixture was stirred at room temperature for 30 minutes, then filtered and the filtrate evaporated to dryness in vacuo. The residue is chromatographed on a column of 80 ml of silica gel, eluting with a 4: 1 by volume mixture of ethyl acetate and methanol. Evaporation of the solvent from the eluate gave the title compound as the free base which was converted to the hydrochloride by dissolving in ether and adding a saturated solution of anhydrous hydrogen chloride in ether until precipitation was complete. After filtration and drying, 1.04 g of the title compound is obtained, m.p. 222-224 ° C.

IR (KBr-technique, μΐη values): 2.97, 3.43,

4.00 (broad band), 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 (methanol): λ _max 245 (ε = 0,653 x 10 ⁴ ),

270 (ε = 0.914 x 10 ⁴ ).

Example 1 a d 2

Following the procedure of Example 1, the following dl-trans derivatives were prepared from the corresponding 3-benzoylpropionic acids using the appropriate starting free bases. The products are isolated as hydrochlorides unless otherwise stated.

X

X Y OF melting point ( ^C C) yield (%) F F H 220 to 223 18 H , H F 239 to 245 39 H CH 2 O amorphous solid (a) 54 F F CH3O 45 to 48.5 (b) 31

Legend:

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

IR (KBr), 2.98, 3.42, 4.07 (broad band), 6.20, 6.26, 6.70, 6.88, 8.04, 8.54 , 9.77, 12.05.

(b) melting point and yield are given for the free base.

Example 3

Following the procedure described in Example 1, the following compounds were obtained using the corresponding starting dl-trans-hexahydro-1H-pyrido [4,3-b] indoles and the correspondingly substituted 3-benzoylpropionic and 4-benzoylbutyric acids:

n X Y OF 3 F p-fluoro m-fluoro 3 F p-fluoro o-methoxy 3 F H p-fluoro 3 H p-fluoro p-methoxy 3 H o-fluorine m-methoxy 3 F H H 3 H m-fluoro H 3 H H m-fluoro 4 F p-fluoro p-fluoro 4 F p-fluoro p-methoxy 4 F o-fluorine H 4 F H H 4 F H m-methoxy 4 H p-fluoro H 4 H m-fluoro o-fluorine 4 H o-fluorine p-methoxy 4 H H o-methoxy 3 H p-fluoro p-fluoro 3 H o-fluorine o-fluorine 3 F m-fluoro p-fluoro 3 H m-fluoro p-fluoro

Example 4 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 acetate

To 5 g 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 hydrochloride in 75 ml of water was added 3 ml of water containing 1.0 g of sodium hydroxide and the liberated base was extracted with 150 ml of diethyl ether. The ether layer was separated, dried over magnesium sulfate and treated with 1 mL glacial acetic acid. The organic solvent and excess acetic acid were evaporated under reduced pressure, the residue was triturated with hexane and filtered.

Other acid addition salts, in particular pharmaceutically acceptable acid addition salts, may also be prepared in an analogous manner.

Example 5

Performance and performance tests

The effects of the compounds of the invention on the main symptoms induced by amphetamine are tested in rats using a scale according to the pattern described by Quinton and Halliwell and Weissman. Groups of 5 rats are placed in covered plastic cages, measuring about 26 cm x 42 cm x 16 cm. After brief cage acclimatization, rats of each group are administered subcutaneously with test compound -a, and after 1, 5 and 24 hours, 5 mg / kg d-amphetamine sulfate is administered intraperitoneally. At 1 hour after amphetamine administration, characteristic rat amphetamine administration was observed in each rat exhibiting movement of the rat around the cage. Based on the amphetamine response at various doses of the test compounds, the effective dose of the appropriate compound required to antagonize or block the caged amphetamine behavior in 50% of the experimental rats (ED 50) can be determined. The time chosen for evaluation is within the time of peak amphetamine effect, which occurs 60-80 minutes after administration of the amphetamine.

The following 4a, 9b-trans compounds were tested as described above for the ability to block the effects of amphetamine on the behavior of test animals. The results obtained are reported as ED 50 values (mg / kg) after the indicated times.

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-? - -fluoro-5- (pfluorophenyl-2- [4-hydroxy-4- (pfluorophenyl) butyl] -1,2,3,4-tetramethyl-4-carbonyl ^(b) 0, 1 to 0.32 0.1 to 0.32 0.32 to 1.0

4avane ^(c) , after 0.32 to 1.0>10> 32

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207813

Legend:

(a) The corresponding 4a, 9b-cis-analog was found to have an ED 50 value of ~ 56 mg / kg after one hour;

(b) U.S. Patent No. 4,001,263;

(c) cis-9- [3- (4-methyl-1-piperazinyl) propylidene] -2- (diethylsulfonamido) thioxanthene (U.S. Pat.

310,553).

Example 6

Tablets

By mixing the following ingredients in the indicated weight ratios, a tablet base is prepared:

sucrose (USP) 80.3 tapioca starch 13.2 magnesium stearate 6.5

To this tablet base is added an amount of trans-8-fluoro-5- (p-fluorophenyl) -2- (4- (p-fluorophenyl) -4-hydroxybutyl) -2,3,4,4a, 5,9b- hexahydro-1H-pyrido [4,3-b) indole hydrochloride to provide tablets containing 1.0, 2.5, 5.0, and 2.5, respectively, after processing as described below. 10 mg of the active substance. The resulting blends are then compressed into 360 mg tablets by conventional compression techniques.

Example 7

Capsule

A mixture is prepared containing the following components:

calcium carbonate (USP) 17.6 secondary calcium phosphate 18.8 magnesium silicate (USP) 5.2 lactose (USP) 5.2 potato starch 5.2 magnesium stearate 0.8

To this mixture was added an additional amount of 0.35 g of magnesium stearate and such an amount of trans-5-phenyl-2- (4-hydroxy-4-phenylbutyl) -2,3,4,4a, 5,9b-hexahydro-1H -pyrido [4,3-b] indole hydrochloride in order to obtain capsules containing 1.0, 2.5, 5.0, respectively, after processing as described below. 10 mg of the active substance.

The prepared blends are filled with conventional hard gelatin capsules in an amount of 350 mg / capsule.

Example 8

Suspension

Prepare a suspension of trans-8-fluoro-5- (fluorophenyl) -2- [4-hydroxy-4- (p-methoxyphenyl) butyl] -2,3,4,4a, 5,9b-hexahydro-1H -pyrido [4,3-b] indole acetate, of the following composition:

active ingredient 25.00 g

70% aqueous sorbitol 741.29 g glycerine (USP) 185.35 g gum arabic (10% solution) 100.00 ml polyvinylpyrrolidone 0.50 g distilled water make up to 1 liter

Various sweetening and flavoring agents may be added to this suspension to improve organoleptic properties. The suspension contains about 25 mg of active ingredient per ml.

Example 9

The sesame oil is sterilized by heating at 120 ° C for two hours and then added to such an amount of powdered trans-8-fluoro-5- (p-fluorophenyl) -2- (4- (p-fluorophenyl) -4-hydroxybutyl] - 2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole hydrochloride to give the resulting suspension containing 0.025% by weight of the active ingredient The solid active ingredient is thoroughly dispersed in the oil using a colloidal The resulting suspension is filtered through a 0.149 mm to 0.057 mm sieve and filled into sterile ampoules, which are then sealed.

Claims (6)

SUBJECT OF THE INVENTION Process for the preparation of trans-5-aryl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indoles of general formula II Y in which the hydrogen atoms attached to the carbon atoms at positions 4a and 9b are trans to each other, each of X and Y, which may be the same or different, represents a hydrogen or fluorine atom, n is 3 or 4 and Z represents an atom hydrogen, a fluorine atom, or a methoxy group, and pharmaceutically acceptable salts thereof, characterized in that the free base is of the general formula V wherein X and Y are from above. is acylated by reaction with a carboxylic acid of formula IV O (IV) in which Z and n are as defined above, or with the acid chloride or bromide, to give the 4a, 9b-trans-hexahydro-χ-carboline derivative of formula III, which is then reduced with lithium aluminum hydride in the presence of an inert solvent and the compound obtained is optionally converted to its pharmaceutically acceptable salt. 2. A process according to claim 1, wherein ethyl ether or tetrahydrofuran is used as the inert solvent. 3. The process of claim 1 wherein the reduction is carried out at room temperature. 4. The process according to claim 1, wherein the acylation is carried out in the presence of an inert organic solvent and a condensing agent. 5. Process according to claim 4, characterized in that dicyclohexylcarbodiimide is used as condensing agent. 6. A process according to any one of Claims 1 to 5 wherein the acylation reaction is carried out at a temperature of from 0 to 30 ° C.