CS207614B2 - Method of making the 4a,9b-trans-hexahydro-gama-carboline derivatives - Google Patents

Description

The present invention relates to a process for the preparation of certain 4a, 9b-trans-hexahydro-γ-carboline derivatives which are useful as starting materials for the preparation of transquilizing active trans-2-subst.-5-aryl-2,3,4,4a; 9b-hexahydro-1H-pyrido [4,3-b] indole derivatives.

After the introduction of reserpine and clilorpromazine in the field of psychotherapy in the early 1950s, great efforts were made to find and develop other tranquilizing agents with improved biological properties. Some of these agents are χ-carboline derivatives also known in the art as pyrido [4,3-b) indole derivatives.

U.S. Pat. No. 3,687,961 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 * * * V} is methyl or ethyl and

R ² 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-χ-carboline nucleus from the starting 1,2,3,4-tetrahydro- γ-carboline by catalytic hydrogenation in the presence of platinum, a well-known method of introducing cis-hydrogen hydrogen atoms to a carbon-carbon double bond. The compounds protected by this patent are neuroleptic agents which are said to be useful in the treatment of schizophrenia.

U.S. Patent No. 3,991,199 discloses hexahydropyrmido [4,3-b] in207614 mines useful as analgesics and sedatives, some of which are of interest as tranquilizing agents, some as muscle relaxants, and many of which exhibit hypotensive efficacy . 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 methyl, methoxy or chloro, phenethyl, 3-phenylpropyl, 3-phenylpropyl substituted in the ring by chlorine, bromine or methoxy, furfuryl, 2-thenyl, alkyl of 1 to 5 carbon atoms, alkenyl of 3 C 5 -C 5 alkynyl, C 3 -C 5 alkynyl, clnamyl, 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, (C6-C8) cycloalkylmethyl, (C6-C8) cycloalkadienylmethyl, (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-en-1-yl) a methyl group.

(bicyclo [2.2.2] hept-2-yl) methyl, (bicyclo] 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 (Dewent No. 00043Y) discloses 5-phenylhexahydro- [beta] -carbolines optionally substituted in the 2- and 4-positions by methyl or ethyl and in the 3-position by a C1-C3 alkyl group , allyl or propargyl. These compounds are useful as antidepressants.

DOS No. 2,631,836 (Derwent No. 09738YJ) recently discloses structurally related octahydropyrido [4 ', 4': 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 -CH 2 CH 2 COCH 3 or -CH 2 CH 2 COC 6 H 5 group, said to be useful as analgesics and tranquilizing agents.

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

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

As mentioned above, the invention relates to a process for the preparation of starting materials used for the process. preparing valuable tranquilizing agents which are enantiomeric and racemic compounds of formula II

wherein the hydrogen atoms attached to the carbons at positions 4a and 9b are in mutual relationship. trans, each of Xi and Yi, which may be the same or different, represents a hydrogen or fluorine atom, n is 3 or 4,

M represents —G—

II o

or.

—CH—, a

OH

WITH

Z 1 represents a hydrogen atom, a fluorine atom or a methoxy group, and pharmaceutically acceptable salts thereof.

The preparation and use of these tranquilizing agents is described in our related Czechoslovak patents Nos. 207 612 - 207 613.

The compounds produced according to the process of the invention correspond to the following general formula III and their preparation is illustrated by the following reaction scheme in which the second reaction step is a process according to the invention.

^ethe y (2) H @ ⁺

(IV)

X

XX

9b

N-R,

N

y (iv) (1) ClCO 2 Cl 2 -

ΜΚΟΗ, Ο ^ ΟΗ / Ηβ

NH

N

(lil)

For economic reasons, the preferred R2 radical is a benzyl group, but other R2 radicals may also be used in the reaction of the above scheme. Examples of such R2 radicals include benzyl radicals substituted in the benzene ring by, for example, one or more substituents selected from the group consisting of methyl, methoxy, nitro and phenyl, and benzhydryl and radicals of the formula - ( CH 2) _n —CH (OH) - (C 6 H 2 J 2) where

Z represents a hydrogen atom, a fluorine atom or a methoxy group and n is 3 or 4.

The reduction of the tetrahydro - / - carbolines of formula V to 4a, 9b-trans-hexahydroderivatives of formula IV is carried out in an ether solvent, usually tetrahydrofuran. An excess of borane-tetrahydrofuran (BH 3 .THFJ), preferably a 100 to 200 mole% excess of the complex, is generally used to ensure complete reduction, although the reaction may be carried out in the range of about -10 ° C to about 80 ° C. at a temperature of about 0 DEG C. to about 65 DEG C. A solution of the starting compound of formula V in tetrahydrofuran is usually added to an ice-cooled solution of BH3, THF, and the mixture is heated to reflux and maintained at this temperature. The reaction is usually carried out in the presence of an inert gas such as nitrogen, after completion of the reaction, the solvent is evaporated and the residue is acidified with an excess of an acid such as 2 to 12 M hydrochloric acid. of acetic acid and 5 M hydrochloric acid, the acidified mixture is usually heated to reflux for 1 to 2 h. The desired product can then be isolated, for example, by evaporation of any remaining ethereal solvent and part of the acid mixture, followed by filtration and washing of the precipitated product. According to an alternative method of isolation of the product of formula IV, the reaction mixture is filtered after reflux, the filtrate is cooled and basified, for example by the addition of sodium hydroxide, potassium hydroxide or sodium carbonate. The basic mixture is extracted with a water-immiscible organic solvent such as chloroform, methylene chloride or benzene, the extract is evaporated and the residue is purified by silica gel column chromatography eluting with, for example, ethyl acetate or mixtures of hexane and ethyl acetate.

Reduction of tetrahydro - / - carbolines by BH3 complex. THF followed by acid treatment leads to hexahydro - / - carbolines in which the hydrogen atoms attached to the carbon atoms at positions 4a and 9b are trans to each other (see, for example, U.S. Patent No. 3,991,199).

The 2-benzyl derivatives of the formula IV are then converted into the corresponding compounds of the formula III containing a hydrogen atom in the 2-position by the process of the invention. The reaction can generally be carried out by treating the compound of formula IV with a molar excess of a lower alkyl chloroformate such as methyl, ethyl, propyl or isobutyl chloroformate, in the presence of a suitable inert organic solvent, followed by alkaline hydrolysis. Because of its ease of availability and efficiency, the preferred chloroformate ester is ethyl chloroformate. By suitable inert organic solvent is meant a solvent which, under the reaction conditions, practically completely dissolves the reactants and does not give rise to by-products. Examples of such solvents include 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.

To the mixture of the starting material of formula IV and the aforementioned inert organic solvent is added about a ten-fold excess of chloroformic acid ester. For economic reasons, a three to five molar excess is preferably used. The resulting mixture is then heated to about 80 to 150 ° C for about 6 to 24 hours or longer, usually at reflux. Suitably, the reaction mixture is refluxed overnight. The resulting reaction mixture is then evaporated in vacuo, the residue taken up in a mixture of water and an alcohol, about ten to thirty molar excess (based on the amount of starting material of formula IV) of a base such as sodium hydroxide or potassium hydroxide is added and the resulting mixture heated to boiling. The solvent is evaporated, the residue is partitioned between water and a water-immiscible organic solvent such as chloroform, methylene chloride or ethyl ether, and the organic phase is evaporated to dryness. or may be further purified by conventional techniques such as silica gel column chromatography.

Preparation of starting materials

2-Benzyl-5-phenyl-1,2,3,4-tetrahydro-1'-carboline is prepared by Fischer indole synthesis using Ν, Ν-diphenylhydrazine and N-benzyl-4-piperidone. The starting mono- or difluorosubstituted tetrahydro-γ-carbolines of formula V wherein at least one of X and Y is fluorine and R2 is benzyl are prepared from the corresponding compounds of formula V in which R2 is hydrogen by reaction with a benzyl halide, as benzyl bromide, the starting materials being used in equimolar amounts. The compounds of formula (V) in which R @ 2 is hydrogen are prepared as described in U.S. Patent No. 4,001,263.

Other starting materials are either commercially available, or their preparation is specifically described in the chemical literature, or can be prepared by methods known per se. For example, phenylhydrazines are commercially available or can be prepared by reduction of phenyldiiazonium salts as described by Wagner and Zook in "Synthetic Organic Chemistry", John Wiley and Sons, New York. N. Y., 1956 (see Chapter 26). The 1-substituted 4-piperidones are commercially available or can be prepared as described by McElvain and Rorlg in J. Am. Chem. Soc., 70, 1826 (1948).

As mentioned above, the basic compounds of the invention may form acid addition salts. Said basic compounds are converted to 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 re-converted to the same or other acid addition salts.

The invention is illustrated by the following non-limiting examples.

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

To a solution of 0.140 mol of borane in 150 ml of tetrahydrofuran cooled to 0 ° C, placed in a three-necked round-bottom flask equipped with a magnetic stirrer, thermometer, condenser and dropping funnel, is added under stirring a solution of 23.9 g (0.071 mol). -benzyl-5-phenyl-1,2,3,4-tetrahydropyrido [4,3-b] indole in 460 ml of dry tetrahydrofuran. The last granular solution was added at a rate such that the reaction temperature was maintained below 9 ° C. After the addition was complete, the resulting mixture was heated to reflux and maintained at this temperature for 1 hour. The solvent was evaporated in vacuo, the white solid residue was suspended in 40 ml dry tetrahydrofuran and the suspension was initially slowly warmed with 180 ml of a mixture of equal parts of acetic acid and 5 N hydrochloric acid. The resulting suspension was refluxed for 1 hour, then cooled and tetrahydrofuran and some of the acetic acid evaporated to precipitate a white solid, which was filtered off, washed with water and resuspended in tetrahydrofuran. The suspension is filtered, the filter residue is washed with ethyl ether and air-dried. 16.7 g (63%) of the desired trans-isomer of melting point 256 DEG-260 DEG C. are obtained.

Evaporation of the mother liquors gave an additional 7.2 g of product contaminated with a small amount of the cis-isomer.

If the above procedure is repeated except that appropriately substituted 2-benzyl-5-phenyl-1,2,3,4-tetrahydropyrido [4,3-b] indole is used as starting material, it is obtained in an analogous manner the following 4a, 9b-trans derivatives in the form of hydrochlorides:

X Y

H p -fluorine

F H

F p-fluoro

H o-flupr

F m -fluorine

F o -fluorine

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

A. To a solution of 5.6 g (12.4 mmol) dl-trans-8-fluoro-5- (p-fluorophenyl) -3- [4-hydroxy-4- (p-fluorophenyl) butyl] -2,3 4,4a, 5,9b-hexahydro-1H-pyrido {4,3-b] indole in 40 ml of 10 ml of toluene was added 5.3 ml (55.7 mmol) of ethyl chloroformate and the resulting mixture was refluxed overnight. 200 ml of ethanol / water (9: 1 by volume) was added to the resin residue, after dissolution of the resin residue, 15 g of potassium hydroxide was added, and the resulting mixture was refluxed overnight. The organic extracts were washed with water and dried over sodium sulfate, evaporated to dryness, the oily residue taken up in ethyl acetate and chromatographed on a silica gel column, eluting first with ethyl acetate to remove the by-products, then the mixture is eluted with a mixture of equal volumes of ethyl acetate and methanol Fractions containing the title compound were combined and evaporated to dryness to give 1.5 g (43%) of a yellow gum which crystallized on standing. Mp 115-117 ° C.

B. Alternatively, the title compound may be obtained by dl-trans-2-benzyl-8-fluoro-5- (fluoro-phenyl) -2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] Jindole hydrochloride is refluxed in the presence of an excess of ethyl chloroformate or methyl, isopropyl or n-butyl chloroformate, after which the reaction product is hydrolyzed and worked up as described above.

Example 3

Similarly, the following products were obtained as described in Example 2A or 2B using the appropriate starting materials:

dl-trans-5- (pfluorophenyl) -2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole, dl-trans-8-fluoro-5-phenyl- 2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole, dl-trans-5- (o-fluorophenyl) -2,3,4,4a, 5,9b- hexahydro-1H-pyrido [4,3-b] indole, dl-trans-5- (of fluorophenyl) -8-fluoro-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4, 3-b] indole, dl-trans-5- (m-fluorophenyl) -8-fluoro-2,3,4,4a, ^{5,9b-hexahydro,} dihydro-lH-pyrido (4,3-b] indole and dl-trans-5- (m-fluorophenyl) -2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole.

Claims (5)

SUBJECT A process for the production of 4a, 9b-trans-hexahydro-χ-carboline derivatives of the general formula III wherein each of X and Y, which may be the same or different, represents a hydrogen atom or a fluorine atom, characterized in that 4a, A 9b-trans-hexahydro-γ-carboline derivative of the general formula IV wherein X and Y are as defined above and R 6 represents a benzyl group, a benzhydryl group, a benzyl group of YNALEZU substituted with methyl, methoxy, nitro or phenyl, or a radical of formula CeH4CH-Z _{(CH2) n} -, OH in which Z represents a hydrogen atom, a fluorine atom or a methoxy group and n has a value of 3 or 4, is reacted with a molar excess of a lower alkyl chloroformate in the presence of an inert organic solvent and subjected to alkaline hydrolysis. 2. A process according to claim 1 wherein the lower alkyl chloroformate is ethyl chloroformate. 3. The process according to 1 or 2, characterized in that toluene is used as the inert organic solvent and the reaction is carried out under reflux of the reaction mixture ¹ . 4. A process according to any one of claims 1, 2 and 3, wherein the starting materials of formula (IV) above are used, wherein R2 is benzyl and X and Y are as defined above. 5. A process according to any one of claims 1 to 4, wherein the alkaline hydrolysis is carried out under reflux with sodium hydroxide or potassium hydroxide. * Sevarografla, n. P., Xivod 7, Most