NO151862B - NEW HIGH-DETERGENT 5-ACRYL-2,3,4,4A, 5,9B-HEXSAHYDRO-1H-PYRIDO (4,3-B) -INDEAL DERIVATIVES SUITABLE FOR PREPARING SOFT-HEXING HYDRO-X CARBOLINE DERIVATIVES - Google Patents

Description

After the introduction of reserpine and chlorpromazine into psychotherapeutic medicine in the early 1950s, extensive efforts have been made to find other sedatives with improved biological profiles, several of which are γ-carboline derivatives, also known as derivatives of pyrido[4 ,3-b]indole.

According to Norwegian patent 150,204, certain trans-2-substituted-5-aryl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole derivatives are prepared which are very effective as sedatives .

The compounds produced according to patent 150,204 are the enantiomeric and racemic compounds with the formula

and pharmaceutically acceptable salts thereof, wherein the hydrogen atoms attached to the carbon atoms in the 4a and 9b positions are in a trans relationship to each other, and X and Y are the same or different and are each hydrogen or fluorine; M is CHOH, CH=CH or C=O;

when M is CH=CH, n is 2, and when M is C=0 or CHOH, n is 3,

and Z is hydrogen, fluoro or methoxy.

The present invention relates to new compounds which are suitable as starting materials in the production of certain of the above-mentioned compounds of formula II, namely those in which at least one of X and Y

is fluorine.

The new compounds are dextrorotatory 5-aryl-2,3,4,4a,5,9b-hexhydro-1H-pyrido[4,3-b]-indole derivatives with the formula and acid addition salts thereof, where the hydrogen atoms are bound to the carbon atoms in 4a - and the 9b positions are in a trans relationship to each other; one of X 1 and Y 2 is fluorine and the other is hydrogen or fluorine, and preferably X 2 is fluorine and Y 2 is fluorine.

The following reaction scheme illustrates the preparation of the 4a,9b-trans-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]-indole starting materials (in free base form) of formula (X) where X2 and Y^ are as stated above:

For economic reasons, benzyl is a preferred meaning for 1*2- However, other meanings for R2 may also occur in the above scheme, as will be apparent to those skilled in the art.

The reduction of the tetrahydro-Y-carbolines of formula (VIII) to form the 4a,9b-trans-hexahydro compounds of formula (IX) is carried out in an ether solvent, usually tetrahydrofuran. To ensure complete reduction, a molar excess of borane/tetrahydrofuran complex (BH"THF) is usually used, and 100 to 200% molar excess of said complex is preferred. Although the reaction can be carried out at a temperature in the range from about -10 to 80° C., a temperature of from about 0 to 65° C. is preferred. Usually a solution of the starting material of formula (VIII) is placed

in tetrahydrofuran to an ice-cooled solution of BH^"THF. After the addition is complete, the reaction mixture is heated to reflux temperature and maintained at this temperature for a period of about one to two hours or more. The reaction is usually carried out in the presence of an inert gas so as nitrogen. When the reaction is nearly complete, the solvent is evaporated, and the residue is acidified with an excess of an acid such as 2 to 12 molar hydrochloric acid. A preferred acidifying agent is a mixture of equal volumes of acetic acid and 5 molar hydrochloric acid. The acidified mixture is usually heated at reflux temperature for 1 to 2 hours or more. The desired product may then be isolated, for example by evaporation of any remaining ether solvent and some of the acid mixture, and the precipitated product collected by filtration and washed. By an alternative method of isolation of the product (IX), the reaction mixture is filtered after the reflux period, the filtrate is cooled and made alkaline by adding, for example, sodium hydroxide, potassium hydroxide or sodium carbonate. The basic mixture is extracted with a non-water-miscible organic solvent such as e.g. chloroform, methylene chloride or benzene, the extracts are evaporated, and the residue is purified by column chromatography on silica gel by elution with, for example, ethyl acetate or mixtures of hexane/ethyl acetate.

The reduction of tetrahydro-Y-carbolines with BH^THF followed by acid treatment gives hexahydro-T-carbolines in which the hydrogen atoms bound to the carbon atoms in the 4a and 9b positions are in a trans relationship, see e.g. U.S. Patent 3,991,199.

The 2-benzyl compounds of formula (IX) are then converted into the corresponding 2-hydrogen compounds of formula (X). In general, this can be achieved by treating the compound of formula (IX)<1> with a molar excess of a lower alkyl chloroformate ester such as, for example, methyl, ethyl, propyl or isobutyl ester in the presence of a suitable reaction-inert organic solvent, followed by alkaline hydrolysis. Ethyl chloroformate is preferred as chloroformate ester because of its availability and effectiveness. A suitable reaction-inert organic solvent is to be understood as one which will essentially dissolve the reaction components under the reaction conditions without by-products being formed. 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 a ten molar excess of the chloroformate ester is added to the mixture of starting material with formula (IX) in said reaction-initiated organic solvent. For economic reasons, a molar excess of approx. 3 to 5. The resulting mixture is then heated at a temperature from approx. 80 to 150°C, typically at the reflux temperature of the mixture,

for a period of approx. 6 to 24 hours or more. Usually, the reflux treatment is carried out overnight for practical reasons.

, The reaction mixture is then evaporated in vacuo, and the residue is taken up in an alcohol-water mixture, an alkali, e.g. sodium hydroxide or potassium hydroxide, is added for approx. 10-30 molar excess based on the amount of starting material of formula (IX), and the resulting mixture is heated at reflux temperature, conveniently overnight. The solvent is then evaporated, and the residue is distributed between water and a non-water-miscible organic solvent such as chloroform, methylene chloride or

ethyl ether, and the organic phase is evaporated to dryness. The remaining product of formula (X) can be used as such or purified further by standard methods known per se, e.g. by column chromatography on silica gel.

The optical isomers of the new amine (X) are obtained by cleavage of the racemic compounds. The cleavage is carried out using a salt formed between the amine (X) and an optically active acid. Although a number of acids are known which are useful for the cleavage of amines, see e.g. Fieser et al., mentioned above, are preferred acids which cause a slight cleavage of the amine (X), the optical isomers (D- and L-) of N-carbamoylphenylalanine. The latter is obtained by reacting the isomeric phenylalanines with sodium cyanate by methods known per se. The cleavage is achieved by reacting one of the isomeric N-carbamoylphenylalanines, e.g. the L-isomer, but a racemic compound of formula (X) in equimolar amounts in the presence of a suitable reaction-initiated solvent to form a homogeneous solution of the salts. Upon cooling, the salt of one of the optical isomers of (X) is obtained as a crystalline, solid substance which can optionally be purified further. The mother liquors, which mainly contain the salt of the other isomer, are evaporated to dryness, and the salt is decomposed with an aqueous base such as e.g. sodium carbonate, potassium hydroxide or calcium carbonate, and the free base is extracted with a water-miscible solvent, typically ethyl acetate, dried, and the solvent is evaporated to give a residue which is enriched with the other isomer of the amine (X). This residue is then taken up in a reaction-inert solvent and treated with an equimolar amount of the other isomer of N-carbamoylphenylalanine, e.g.

the D-isomer, and the solution is cooled to precipitate crystals

of the N-carbamoylphenylalanine salt of the second isomer of formula (X).

Each of the salts containing a single enantiomer of the amine (X) is then decomposed as described above to

give respectively the approximately pure dextrorotatory and levorotatory isomers of (X).

The compound according to the invention with formula (X) can be converted into compounds with a sedative effect which are the enantiomeric and racemic compounds with the formula.

and pharmaceutically acceptable salts thereof, where the hydrogen atoms bound to the carbon atoms in the 4a and 9b positions are in a trans relationship to each other, and X2 and Y2 are as indicated above;

and Z is hydrogen, fluoro or methoxy.

This conversion is described in the original application to which reference is made.

The mono- or di-fluoro-substituted tetrahydro-y-carboline starting materials of formula (VIII) where at least one of X2 and Y2 is fluorine and R2 is benzyl, are prepared from the corresponding compounds of formula (VIII) where R2 is hydrogen, by reaction with a benzyl halide so as benzyl bromide, in equimolar amounts. The necessary compounds of said formula (VIII, R2=H' are prepared as described in U.S. Patent 4,001,263.

Example I

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

A. To a solution of 5.6 g (12.4 mmol) of dl-trans-8-fluoro-5-(p-fluorophenyl)-2-[4-hydroxy-4-(p-fluorophenyl)butyl]-2, 3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole in 40 ml of toluene was added 5.3 ml (55.7 mmol) of ethyl chloroformate. The resulting mixture was refluxed overnight and then evaporated to dryness to give a residual gum. 200 ml of a 9:1, by volume, mixture of ethanol and water was added to the rubber. After the mixture dissolved, 15 g of potassium hydroxide was added and the resulting mixture was refluxed overnight. The solvent was evaporated in vacuo and the residue was partitioned between water and chloroform. The organic extracts were washed with water, dried over sodium sulphate and evaporated to dryness. The remaining oil was taken up in ethyl acetate and passed through a silica gel column by first eluting with ethyl acetate to remove byproducts and then eluting the desired product with 1:1, by volume, ethyl acetate/methanol. The 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, m.p. 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 is refluxed -hydrochloride in the presence of an excess of ethyl chloroformate or the corresponding methyl, isopropyl or n-butyl chloroformate esters, is then hydrolysed and worked up by the method described above to give the title compound.

Example II

By using the appropriate starting material in each case and applying the procedure according to Example IA or IB, the following products are prepared in a similar manner: dl-trans-5-(p-fluorophenyl)-2,3,4,4a,5 ,9b-hexahydro-1H-pyrido[4,3-b]indole, hydrochloride salt, m.p. 235-238°C dl-trans-8-fluoro-5-phenyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole, hydrochloride salt, m.p. 244-246°C.

Claims (1)

Dextrorotatory 5-aryl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]-indole suitable for the preparation of sedative hexahydro-X-carboline derivatives of the formula and pharmaceutically acceptable salts thereof, wherein the hydrogen atoms bonded to the carbon atoms in the 4a and 9b positions are in a trans relationship to each other, one of and Y- being fluorine and the other is hydrogen or fluorine; and Z is hydrogen, fluorine or methoxy, characterized by the formula and acid addition salts thereof, where the hydrogen atoms bonded to the carbon atoms in the 4a and 9b positions are in a trans relationship to each other; and X 2 and Y 2 are as indicated above, and preferably X 2 is fluorine and Y 2 is p-fluorine.