CS207612B2 - Method of making the trans-5-aryl-2,3,4a,5,9b-hexa-hydro-1h-pyrido 4,3-b indoles - Google Patents

Abstract

5-Phenyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indoles, which are substituted in position 2, and their salts of formula I, the symbols of which are explained in Claim 1, are described. These compounds and their salts are therapeutically active and can be used as medicaments for controlling schizophrenic symptoms. The pharmaceutical compositions are also described. The new compounds and their salts can be obtained by processes which are especially distinguished from others by the formation of the substituent in position 2; the latter is obtained by processes which each contain a reduction stage, from compounds which already have the pyridoindole system. <IMAGE>

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

After the introduction of reserpine and chlorpromazm into medicine in the field of psychotherapy in the early 1950s, a great deal of effort was devoted to the search and development of further antitumor agents with better biological properties. Some of these agents are γ-carboline derivatives also known in the art as pyridof4,3-b] indole derivatives.

U.S. Pat

687,961 discloses 8-fluoro-2- [3- (4-fluorophenylanilino) propyl] -1,2,3,4-tetrahydro-γ-carboline 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 β-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 represents a methyl or ethyl group, and

R ^{2 3} is hydrogen, methyl or ethyl.

There is no mention of the stereochemical arrangement of the hydrogen atoms at the 4a and 9b positions in this work, but their relative arrangement could be expected to be cis due to the formation of the hexahydro-γ-carboline nucleus from the starting 1,2,3,4-tetrahydro-γ -carboline by catalytic hydrogenation in the presence of platinum, which is a known method of introducing hydrogen atoms in the cis configuration at the 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 if ^Y is trifluoromethyl, X is ^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 chlorine, phenethyl, 3-phenylpropyl, 3-phenylpropyl substituted in 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, ring substituted cinnamyl, bromine 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 of 6 to 8 carbon atoms (C--C cyklo) cycloalkadienylmethyl group (C až-Copr-), (2,3-dimethylcycloprop-2-en-1-yl) methyl, exo-7-norarylmethyl, (cis-1,6-dimethylendo- 3-norocaren-7-yl) methyl, (4-methylbicyclo [2.2.2] oct-1-yl) methyl, (4-methylbicyclo [2.2.2] oct-2-ene) 1-yl) methyl, (bicyclo [2.2.2] hept-2-yl) methyl, (bicyclof 2,2,2] hept-2-en-5-yl) methyl, 1-adamantylmethyl or 2-adamantylmethyl, and pharmaceutically acceptable salts thereof.

More recently, Belgian Patent Specification No. 845,368 (Derwent No. 00043Y) discloses 5-phenyl-hexahydro- [beta] -carbolines optionally substituted in the 2- and 4-positions by a methyl or ethyl group and at the 3-position by an alkyl group having from 1 to 4 carbon atoms. C 3 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] indole [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 5 or -CH 2 CH 2 COC 6 H 5. These substances are said to be useful as analgesics and tranquilizing agents.

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

wherein X ^b and Z ^b · represent a hydrogen atom or a fluorine atom, and R ^b is as defined above ^and R symbol.

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

Valuable tranquilizing agents produced by the process of the invention are enantiomeric and racemic compounds of formulas II and III.

wherein 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, m is 2 or 3 and Z represents a hydrogen atom, a fluorine atom or a methoxy group, and pharmaceutically acceptable salts thereof.

The products of the present invention may be used to treat the manifestation of schizophrenia in a mammal by administering to a mammal in need thereof, orally or p-arenterally, a transquilizing effective amount of a compound of formula II and III.

The invention further provides tranquilizing pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a compound selected from the group of compounds of Formulas II and III.

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

Particularly preferred tranquilizing agents of the invention are the enantiomers and racemic mixtures of the compounds mentioned. in the following overview:

trans-8-fluoro-5- (pfluorophenyl-2- [4-hydroxy-4- (pfluorophenyl) butyl] -2,3,4,4a, 5,9a-hexahydrol-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, - R, R, R, R, R ', R &apos;, R &apos; indole, trans-5-phenyl-2- (4-hydroxy-4-phenylbutyl) -2,3,4,4a, 5,99-hexahydro-1H-pyrido [4,3-b] indole, trans-8 -fluoro-5- (p-fluorophenyl) -2- (4-hydroxy-4-phenylbutyl) -2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-a] -bj indole, trans-8-fluoro-5- (p-fluorophenyl) -2- [4- (p-fluorophenyl) -3-butenyl] -2,3,4,4a, 5,9b-hexahydro-1H -pyrido [4,3-b] indole, trans-8-fluoro-5- (p-fluorophenyl) -2- [4- (p-methoxyphenyl) -3-butenyl) -2,3,4, 4a, 5,9b-Hexahydro-1H-pyrido) 4,3-b] indole, trans-8-fluoro-5- (of fluorophenyl) -2- (4-hydroxy-4- (pfluorophenyl) butyl) -2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole, trans-5-phen yl-2- [4-hydroxy-4- (pfluorophenyl) butyl] -2,3,4,4.a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole and trans-8 -fluoro-5- (of fluorophenyl) -2- [4- (p-fluorophenyl) -3-butenyl] -2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4, 3-b] indole.

In accordance with the invention, the 4,99-trans compounds of formula II in admixture with the corresponding dehydrated compounds of general formula III are prepared by the reaction illustrated by the following reaction scheme:

(1) BH $ / ether (2) H + ’

OF

In this reaction scheme, X, Y, Z, n and m have the meanings given above.

The reaction with borane is carried out in an ether solvent, preferably tetrahydrofuran. The products of formulas II and III are then separated, for example, by silica gel column chromatography.

The relative amounts of the resulting products of formulas II and III depend on the amount of acid used, for example hydrochloric acid, and on the reflux time after the reduction with the BHH complex. THF. Higher amounts of acid and longer refluxing favorably result in the formation of the dehydrated product of Formula III, while lower amounts of acid and shorter reflux times promote product formation of Formula II.

Acidification is usually carried out by treatment with an excess of acid, for example 2 M to 12 M hydrochloric acid. A preferred acidic reagent is a mixture of equal volumes of acetic acid and 5 M hydrochloric acid. The acidified mixture is generally heated to reflux for 1 to 2 hours, or even longer.

The compounds of formula II may also serve as starting materials for the preparation of the free bases of the formula

This preparation of the free bases is carried out, for example, using ethyl chloroformate followed by alkaline hydrolysis.

By oxidizing the compounds of formula II using reagents and conditions known to selectively convert secondary alcohols to the corresponding ketones, new products of formula IV are obtained

in which. X, Y, Z and n are as defined above.

Examples of oxidizing agents that can be used for this reaction include potassium permanganate, potassium dichromate and chromium trioxide, with chromium trioxide in the presence of pyridine being the preferred reagent. The reaction is carried out using a preferred reagent by adding the starting alcohol of formula (II) in an inert solvent such as dichloromethane, chloroform or benzene to a mixture containing up to 10 molar excess of chromium trioxide and a similar large excess of pyridine and stirring. , usually at room temperature, until the reaction is complete. Generally, a reaction time of about 15 minutes to 1 hour is sufficient. The product is isolated, for example, by filtering off the insoluble material, extracting the filtrate with a dilute aqueous base such as sodium hydroxide solution, drying the organic layer and evaporating it to dryness. Optionally, the resulting product can be further purified, for example by column chromatography.

An alternative process for the preparation of compounds of formula (II) is described in our co-pending Czechoslovak patent specification No. 207,614.

The starting tetrahydrocarbolines of the formula I are described in U.S. Pat. No. 4,001,263.

As mentioned above, the basic compounds produced by the process 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, the reaction of the acid addition salts with an equivalent amount of an aqueous solution of a base, for example an alkali metal hydroxide, an alkali metal carbonate or an alkali metal bicarbonate, or an equivalent amount of the metal cation forming with the anion. acid insoluble precipitate, regenerates the corresponding free base. The bases thus regenerated can then be converted again into the same - or - other acid addition salts.

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

Examples of acids giving pharmaceutically acceptable anions include hydrochloric acid, hydrobromic acid, hydrogen chloride, nitric acid, sulfuric acid, sulfuric acid, phosphoric acid, acetic acid, lactic acid, citric acid, tartaric acid, succinic acid, maleic acid. and gluconic acid.

As mentioned above, the compounds of the present invention can be used therapeutically in mammals as a tranquilizing agent.

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 the tranquilizing activity of the compounds of this group, which achieve excellent correlations of the observed results with human efficacy, consist in antagonizing amphetamine-induced symptoms in rats, as described by A. Weissman et al. in J. Pharmacol. Exp. Ther., 151, 339 (1966) and Quinton et al. in Nature, 200, 178 (1963).

The 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 clays, etc. as carriers. Furthermore, the compounds may be administered in the form of elixirs or suspensions for oral administration in which the active ingredients are combined. emulsifiers and / or 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 should contain other soluble substances, such as sodium chloride or glucose, for isotonization.

While the compounds of the present 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, which are gradually increased until the optimum level is reached. Often, when administered orally, greater amounts of active ingredient than parenteral administration are required to achieve the same effects.

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

All of the compounds of the invention contain at least two asymmetric centers resulting in a reduction of the double bond at positions 4a, 9b to a saturated trans-system. The invention includes both racemates and individual enantiomers. Furthermore, when a substituent at the 2 (R) position contains a moiety that may exist in stereoisomeric forms, all resulting diastereoisomers are within the scope of the invention.

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-8-fluoro-5- (pfluorophenyl) -2- [4-hydroxy-4- (pfluorophenyl) butyl] -2,3,4,4a, 5,9b-hexahydro -1H-pyrido [4,3-b Jindole hydrochloride and dl-trans-8-fluoro-5- (pfluorophenyl) -2 [4- (pfluorophenyl 1-3-butenyl)] -2,3,4 4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole hydrochloride

A 1000 ml reaction flask equipped with a magnetic stirrer and dropping funnel was charged with 177 ml of 0.9 M borane in tetrahydrofuran under nitrogen. The solution is cooled in ice and the cold solution is stirred over. A solution of 25 g (0.0555 mol) of 8-fluoro-5- (p-fluorophenyl) -2- [4-hydroxy-4- (p-fluorophenyl) butyl] -2,3,4,4, 5-tetrahydropyrido [4,3-b] indole in m.p.

295 ml tetrahydrofuran. The resulting mixture was stirred at room temperature for 20 minutes, then heated at reflux for 2 hours. The reaction mixture was cooled and concentrated in vacuo to a liquid residue, to which was added a mixture of 50 ml of acetic acid and 50 ml of 5 N hydrochloric acid. The addition is accompanied by intensive gas evolution. The resulting mixture was refluxed for 1 hour, then cooled to room temperature and filtered. The filtrate was cooled in ice and basified by the addition of 50% (w / w) sodium hydroxide solution. The basic mixture was extracted twice with 150 ml of chloroform each time, the combined organic layers were dried over magnesium sulfate and evaporated in vacuo to dryness. 25 g of a yellow foam-like residue are obtained which, according to chroinatography, on a thin layer of silica gel

12 za. using a mixture of equal volumes of hexane and ethyl acetate. as solvent system contains two products. The foamed solid residue was subjected to silica gel column chromatography using a mixture of equal volumes of hexane and ethyl acetate as eluent. The individual fractions were monitored by thin layer chromatography. Fractions containing only the faster-moving product, 8-fluoro-5- (p-fluorophenyl) -2- (4- (fluorophenyl) -3-butenyl] -2,3,4,4a, 5,9b-hexahydro The 1H-pyrido [4,3-b] indole was evaporated to dryness, the residue was taken up in acetone and converted to the hydrochloride by adding anhydrous hydrogen chloride in acetone, and the resulting white solid was filtered off and dried to give 1.5 g. 270 DEG-273 DEG.

Fractions containing. slower progressing 8-fluoro-5- (pfluorophenyl) -2- [4-hydroxy-4- (p-fluorophenyl) butyl] -2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole was concentrated, the residue is taken up in ethyl ether and addition of anhydrous hydrogen chloride is converted into the hydrochloride. 10.8 g of the desired hydrochloride · · m.p. 241-245 ^C C.

The proportion of the more rapidly progressing 3-butenyl derivative is increased up to 100% by suitable increase in acidity and heating time of the mixture in acetic acid and hydrochloric acid to reflux.

Example 2

If the procedure described in Example 1 was repeated using 8-fluoro-5- (o-fluorophenyl) -2- (4-hydroxy-4- (fluorophenyl) butyl) -2,3,4,5-tetrahydropyrido [ 4,3-b] indole starting material, trans-8-fluoro-5- (o-fluorophenyl) -2- [4- (p-fluorophenyl) -3-butenes] is obtained more rapidly as a silica gel chromatography component 141 DEG-142 DEG C., and as a slower progressing component of trans-8-fluorine] -2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole. -5- (of fluorophenyl) -2- [4-hydroxy-4- (fluorophenyl) butyl] -2,3 ', 4', 4 ', 4', 4 ', 4'-1H-py mp 195-197 ° C; rido [4,3-b] indole.

Example 3 dl-trans-8-fluoro-5- (p-fluorophenyl) -2-methyl-2,3,4,4a, 5,9b-hexahydro-1H-pyridof 4,3-b] indole hydrochloride

A. A 25 ml flask equipped with a stirrer, dropping funnel and nitrogen purge was charged with 573 mg (2.0 moles).

8-fluoro-5- (p-fluorophenyl) -2,3,4,4a, 5,9b-. -hexahydro-1H-pyridO '(4,3-b) indole, 8 ml of dichloromethane and 0.323 ml (4 mmol) of dry pyridine and a solution of 0.219 ml (2.3 mmol) of ethyl chloroformate was added dropwise at room temperature. After the addition was complete, the mixture was stirred for 1 hour, evaporated in vacuo, and the resin residue was partitioned between 10 ml of 10% hydrochloric acid and 25 ml of ether, and the organic layer was washed with 10 ml of water, dried over magnesium sulfate and evaporated to dryness. to give 707 mg of 8-fluoro-5- (pfluorophenyl) -2-ethoxycarbonyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole, which was used in the next step.

B. A 100 ml flask equipped with a magnetic stirrer, dropping funnel and nitrogen inlet was charged with 10 ml of ethyl ether and 524 mg (13,9 mmol) of lithium aluminum hydride. The suspension is cooled in ice and after stirring for 5 minutes under a nitrogen atmosphere, a solution of 707 mg (1.97 mmol) of the product prepared in paragraph A above in 5 ml of ether is added dropwise over 5 minutes. The resulting mixture was stirred at room temperature for 1 h before being added. to this is added first 3 g of anhydrous sodium sulphate and then slowly about 1 ml of water. After stirring for 30 minutes, the reaction mixture was filtered and the white solid was washed with ether. Evaporate the filtrate to dryness, redissolve the residue in ether and dissolve to completion. precipitation adds a saturated solution of anhydrous hydrogen chloride in ether. Filtration of the precipitate gave 481 mg of the title compound.

IR (KBr-technique, μΐη values):

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 H NMR (CDCl 3, δ values):

1.84 to 2.50 · (4H, m)

2.52 (3 H, s),

2.98 to 3.26 (3H, m),

3.46 to 3.64 (1H, m),

6.50 to 7.46 (7H, m).

Examples of dl-trans-5-phenyl-2- (3- (fluoro-benzoyl) -p-oppt-2,3,4,4a, 5,99-hexahydro-1H-pyrido [4,3-b] indole hydrochloride

25 ml reaction flask equipped with a magnetic flask. with a stirrer and kept under nitrogen, 0.828 ml (8.0 mg, 10.3 mmol) of dry pyridine and 10 ml of dichloromethane are added, and 517 mg (5.17 mmol) of chromium trioxide are added to the solution. After stirring at room temperature for 15 minutes, solution 359 was added in one portion. mg (0.862 mmol) dl-trans-5-phenyl-2- [4-hydroxy-4- (p-fluorophenyl) butyl] -2,3,4,4a, 5,9b-hexahydro-1H-pyridine [4] 3-b] indole free base in 5 mL of dichloromethane. The reaction mixture quickly turned into a brown-colored suspension, which was stirred at room temperature for 30 minutes. The insoluble material was filtered off, washed with dichloromethane, the filtrate combined with the washings and extracted with 20 ml of 10-O / _O sodium hydroxide solution. The organic layer was dried (MgSO 4) and evaporated to dryness in vacuo. The gummy residue was purified by chromatography on. silica gel column using equal volumes of hexane and ethyl acetate as eluent. The fractions containing the desired product were combined, evaporated to a yellow gum which was taken up in ethyl ether, and anhydrous hydrogen chloride was added to the solution. The resulting suspension is evaporated to dryness and the residue is stirred in 3 ml of cold dichloromethane. The resulting colorless solid was filtered and dried to give 20 mg of the title compound, mp 244-246.5 ° C.

Example 5 dl-trans-8-fluoro-5- (p-fluorophenyl) -2- [3- (p-fluorobenzoyl) -propyl] 22,3,4,4a, 5,9b-hexahydro-1 H -pyrido [4,3-b] indole hydrochloride

1.09 g of chromium trioxide are added to 20 ml of dichloromethane - and 1.76 ml (21.9 mmol) of pyridine, introduced in a 100 ml flask, and the resulting dark suspension is stirred at room temperature for 15 minutes. Add 824 mL (1.82 mmol) of dl-trans-8-fluoro-5- (p-fluorophenyl) -2- [4-hydroxy-4- (p-fluorophenyl) butyl] -2 in one portion. 3,4,4a, 5, -9b-hexahydro-1H-pyridO '[4,3-blindol as the free base (prepared from the hydrochloride by basifying the aqueous hydrochloride solution with sodium hydroxide, extraction with dichloromethane · and - evaporation - extracts to dryness) in 10 ml of dichloromethane. The resulting dark brown suspension was stirred at room temperature for 1 hour and then worked up as described in Example 4. 25 mg of the desired product was obtained, m.p. 260 DEG-263 DEG.

Example dl-trans-8-fluoro-5- (p-fluorophenyl) -2- [4-hydroxy-4- (p-fluorophenyl) butyl] -2,3,4,4a, 5,99-hexxhydro 1 H -pyrido-o [4,3-b] indole-α-acetate

To 5 g dl-tr ans-8-fluoro-5- [p-fluorophenyl) -2- [4-hydroxy-4- (p-fluorophenyl) butyl] -2,3,4,4a, 5,99- heeahydro-1H-pyrido [4,3-b] indole hydrochloride - in 75 ml of water, 3 ml of water containing 1.0 g of sodium hydroxide are added, and the liberated base is extracted with 150 ml of diethyl ether. The ether layer was separated, dried over magnesium sulfate and treated with 1 mL of glacial acetic acid. The organic solvent and excess acetic acid are evaporated under reduced pressure, the residue is triturated with hexane and filtered.

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

Example 1 a d 7

Performance and results of efficacy tests

The effects of the compounds of the invention on the main amphetamine-induced symptoms were 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 with dimensions of 26 cm x 42 cm x 16 cm. After brief cage acclimatization, rats from each group are administered subcutaneously with the test compound and, after 1, 5 and 24 hours, intraperitoneally 5 mg / kg d-amphetamine sulfate. 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 response of amphetamine administration at various doses of test compounds, the effective dose of the respective compound required to antagonize or block the characteristic behavior after amphetamine administration in the cage movement in 50% of the experimental rats (ED 50) can be determined. The time selected for evaluation falls within the time of peak amphetamine effect which is manifested 60-80 minutes after administration of the amphetamine.

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

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(a) The corresponding 4a, 9b-cis-analog was found to have an ED50 of ~ 56 mg / kg after 1 hour;

(b) ED50 after hours <0.32, after - 72 hours <0.32;

(c) U.S. Patent No. 3,991,199;

(d) Not tested;

(e) U.S. Patent No. 4,001,263; (f) cis-9- [3- (4-methyl-1-piperazinyl) pr 0-pylidene] -2- (dimethylsulfonamido) thioxanthene (U.S. Pat. No. 3,310,553).

Example 8

Tablets

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

sucrose (USP) 80.3 tapioca starch13.2 magnesium stearate 6.5

To this tablet base is added an amount of trans-8-fluoro-5- (p-fluorophenyl) -2- (4- (fluorophenyl) -4-hydroxybutyl) -2,3,4,4a, 5,99- hexxhydro-1H-pyrido [4,3-b] indole hydrochloride to obtain tablets containing 1.0, 2.5, 5.0 and 10 mg of the active ingredient, respectively, after processing as described below. by compression molding into tablets weighing 360 milligrams.

Example 9

Capsule

A mixture is prepared containing the following components:

calcium carbonate (USP) 17.6 secondary calcium phosphate18.8 silicate. Magnesium (USP) 5.2 Lactose (USP) 5.2 Potato starch5.2 Magnesium stearate0.8

To this mixture was added an additional 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-hexahydrate. o-1H-pyrido [4,3-b] in (do'-1-hydrochloride) to obtain, after the treatment described below, capsules containing 1.0, 2.5, 5.0 and 10 mg of the active ingredient, respectively.

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

Example 10

Suspension

Prepare a suspension of trans-8-fluoro-5- (p

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

active ingredient 25.00g

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

Various sweeteners 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 11

Sesame oil is sterilized by heating at 120 ° C for 2 hours, then added trans-8-fluoro-5- (pfluorophenyl) -2- (4- (pfluorophenyl) -4-hydroxybutyl) -4- 2,3,4,4a, 5,9b-eexahydro-1H-pyrido [4,3-b] indole hydrochloride, so that the resulting suspension contained -0.025% by weight of the active ingredient. dispersed using a colloid mill. the resulting suspension was filtered through a ^sieve, mesh size 0.149 to 0.057 mm and the proportion těmito- trapped between screens fills DO- sterile ampoules which are then sealed.

The following Examples A to C illustrate the preparation of the starting materials.

Example A

8-fluoro-5- (p-fluorophenyl) -1,2,3,4-tetrahydro-4-carboline

I. 8-Fluoro-2-ethoxycarbonyl-1,2,3,4-etrahydro-γ-carboline

A mixture of 15.9 g (0.093 mol) of N-ethoxycarbonyl-4-piperidone and 15.1 g (0.093 mol) of p-fluorophenylhydrazine hydrochloride in 150 ml of ethanol was refluxed for 2 hours. The reddish reaction mixture was cooled and filtered, and the filtered solid was washed with a small amount of cold 95% ethanol. 169 DEG-170 DEG C. The analytical sample melts after recrystallization from aqueous ethanol at 169 DEG-170 DEG.

Analysis - For - C 14 H 15 O 2 N 2 F calculated:

64.1% C, 5.8% H, 10.7% N;

found ·:

% H, 5.8%;% N, 0.6%.

II. 8-fluoro-5- (p-fluorophenyl) -2-ethoxycarbonyl-1,2,3,4-tetrahydro-γ-carboline

To 30 ml of N-methyl-4-pyrrolidone was added

3.45 g (0.013 mol) of 8-fluoro-2-ethoxycarbonyl-1H-tetrahydro-γ-carboline, 7.8 g (0.045 mol) of p-fluorobromobenzene, 4.14 g (0.014 mol) of copper (I) bromide and 1.5 g (0.014 mol) of sodium carbonate, and the resulting mixture was heated in an oil bath at 200 ° C for 6 hours. The reaction mixture was allowed to cool to room temperature overnight and then poured into 300 ml of water containing 60 ml of ethylenediamine. After the addition of 200 ml of benzene, the resulting two-phase system was filtered through a pad of diatomaceous earth and the filtrate was extracted with several portions of a total volume of 700 ml of benzene. The extracts were combined, washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate. Evaporation of the solvent gave the crude product as a dark oily residue.

The crude product was taken up in benzene and chromatographed on a silica gel column using 10% ethyl acetate in benzene as eluent. Fractions 11-16 (about 10-25 ml each) containing p-fluorobromobenzene were pooled and discarded. Fractions 16-38 were combined and concentrated in vacuo to an oily residue which solidified on standing overnight at 5 ° C. The product (3.5 g, 76% yield) was triturated with pentane and filtered. The analytical sample melts after recrystallization from pentane at 118-120 ° C.

Analysis calculated for C20H18O2N2F2:

64.7% C, 5.1% H, 7.9% N; found:

67.4% C, 5.2% H, 7.8 o / ₀ · N.

III. 8-Fluoro-5- (p-fluorophenyl) -1,2,3,4-dihydro-γ-carboline

Suspension · 3,56 g ·. (0.01 mol) 8-fluoro-5- (p-fluorophenyl) -2-ethoxycarbonyl-1,2,3,4-tetrahydro-γ-carboline, and 8.2. g (0.146 mol) of potassium hydroxide in 53 ml of ethanol containing 5 ml of water is heated at reflux overnight. . a further 3.0 g of potassium hydroxide are added thereto and heating is continued for 23 hours. The resulting brownish solution was cooled, concentrated to dryness in vacuo and partitioned between water and diethyl ether. The aqueous layer was re-extracted with ether, the ether layers were combined, washed with a saturated solution. Sodium chloride and dried over magnesium sulphate. Evaporation of the solvent gave 2.6 g of the desired product as an orange solid, m.p. 125-127 ° C. The analytical sample melts after recrystallization from pentane at 127-128 ° C.

Calcd for C17H14N2F2:

71.8% C · 5.0% H · 99% N:

found:

71.6% -C, 5.1% H, 10.2%.

The hydrochloride is prepared by introducing hydrogen chloride into a solution of the free base in diethyl ether and has a melting point of 270-272 ° C.

Example B

2-Benzyl-8-fluoro-5- (p-fluorophenyl) -1,2,3,4-tetrahydro-γ-carboline

To a solution of 1,4-g (4,9 mmol) of 8-fluoro-4-fluorophenyl) -1,2,3,4-61-4-tetrahydro-carbonone and 1.02 g (7.4 mmol) of potassium carbonate in 10 ml of dimethylformamide, heated to 60 [deg.] C., is added dropwise with stirring 1.01 g (5.9 mmol) of benzyl bromide in 10 ml of the same solvent. After heating for one hour, the reaction mixture is poured into 200 ml of a 2% aqueous potassium carbonate solution and the resulting solution is extracted three times with 200 ml of benzene each. The combined extracts were washed successively with water and a saturated sodium chloride solution, dried over magnesium sulfate, and the solvent was evaporated in vacuo. . The oily residue which crystallizes on standing is triturated with hexane and the product is filtered off.

Example

8-Fluoro-5- (p-fluorophenyl) -2- [4- (p-fluorophenyl) -4-hydroxybutyl] -1,2,3,4-tetrahydro-ylcarboline hydrochloride

I. Suspension 2.84 g (0.01 mol) 8-fluoro-5- (p-fluorophenyl) -1,2,3,4-tetrahydro-7-carboline, 2.8 g (0.01 mol) of ω-chloro-p-fluorbulyrophenone, 3.15 g (0.03 mol) of sodium carbonate and 50 mg of potassium iodide in 50 ml of 4-methyl-r-pentanone are heated for 15 hours under stirring, and After working up the reaction mixture as described in Example B, 2.6 g of 8-fluoro-5- (p-fluorophenyl) -2- [3- (p-fluorobenzoyl) propyl] -1,2,3,4- of tetrahydro-carbonyl in the free base form with a melting point of 150 to 155 ° C.

To 846 mg (22.4 mmol) of sodium borohydride in 50 ml of ethanol was added dropwise 2.5 g (5.6 mmol) of the above-prepared γ-carboline in a sticky solution in 80 ml of ethanol and 20 ml of lelrahydrofuran at high speed. under reflux. After the addition was complete, the mixture was refluxed for an additional hour and then cooled to room temperature. The supernatant is poured into 300 ml of water and the organic solvents are removed from the aqueous phase by evaporation in vacuo. The residue is extracted with dichloroethane and the combined extracts are washed with a saturated sodium chloride solution, dried over magnesium sulfate, the solvent is evaporated in vacuo and the residue is dissolved in a mixture of ethyl ether and dichloro ether. Carefully introduce hydrogen chloride lacquer into the decomposition until a precipitate formed. The resulting title compound was filtered and dried. The product has a melting point of 249 to 250 ^° C.

Claims (6)

SUBJECT OF THE INVENTION 1. A process for the preparation of a compound of formula (II) and (III) wherein hydrogen atoms are bonded to atoms. the carbon at positions 4a and 9b are in alignment with each other; each of the X and Y symbols which may be missed or different, denotes hydrogen or fluorine, n is 3 or -4, m is 2, or 3 and Z represent a hydrogen atom, a fluorine atom or a methoxy group, and their pharmacologically usable salts, characterized in that the tetrahydro-carboline of the general formula (I) as defined above is reacted with borane in an inert manner; 10 to 80 [deg.] C. and treated with acid, the resulting compounds of formulas II and III are separated, and optionally converted into pharmaceutically acceptable salts by treatment with acid. 2. A process according to claim 1, wherein the inert organic solvent is ethyl ethyl ether or hydrofuran. 3. Method according to claim 1 or 2, characterized in · LIM that the reaction with borane is performed at a better _LE from 0 to 65 ° C. 4. A process according to any one of claims 1 to 3, wherein the acid is a mixture of hydrochloric acid and acetic acid. 5. The process of claim 4, wherein a mixture of equal volumes of acetic acid and 5M hydrochloric acid is used. 6. The process of claim 4 wherein the mixture is heated to reflux.