NO138407B - ANALOGICAL PROCEDURE FOR THE PREPARATION OF PHARMACOLOGICALLY ACTIVE MORPHOLINE DERIVATIVES - Google Patents

Abstract

Analogous process for the preparation of pharmacologically active mor.fo 1 inder ivater.

Description

This invention relates to analog method for

production of morpholine derivatives that possess psychotropic properties.

According to the invention, a

morpholine derivative with the formula:

where A means an ethylene (-OI^CH,,-) or vinylene radical (-CH=CH-),

and X means a phenyl radical which is optionally substituted with one or two substituents selected from halogen atoms, alkyl and alkoxy radicals with 1 to 6 carbon atoms and phenoxy radicals with 6 to 10 carbon atoms, the phenoxy radicals themselves being optionally substituted with one or two substituents selected from halogen

atoms and alkyl radicals having 1 to 4 carbon atoms, and the pharmaceutically acceptable acid addition salts thereof.

It will be seen that the morpholine derivative prepared according to

the invention contains an asymmetric carbon atom, the one marked 2 in formula I. The racemic form of the compound with formula I can therefore be split into two optically active forms. It is to be understood that this invention includes the racemic form of compounds of formula I and any optically active enantiomeric forms which possess the useful properties of the compounds prepared according to the invention, as hereinafter indicated, and it is generally generally known how to split a racemate into its optically active isomers and determine the biological properties thereof.

It should also be understood that when A is a vinylene radical,

then it can be in cis- or trans-form, and that the position of the possible substituent in the phenyl ring in X is defined in accordance with the usual numbering system in which the carbon atom directly bonded to A is number 1.

A special meaning for the possible substituent in X is a fluorine, chlorine or bromine atom or a methyl, methoxy, ethoxy or phenoxy radical.

A particular value for A is an ethylene or trans-vinylene radical.

Special groups of compounds produced according to the invention are the following: Those where X carries a single possible substituent. Such where A means an ethylene or trans-vinylene radical and X means a phenyl radical which is unsubstituted or which is substituted with a fluorine, chlorine or bromine atom or a methyl,

-methoxy or phenoxy radical in the 2- or 4-position.

Such where A means an ethylene radical and X means a phenyl radical which is unsubstituted or which is substituted by a phenoxy radical in the 2-position, or in which A means a trans-vinylene radical and X means a phenyl radical which is unsubstituted or which is substituted by a chlorine - or bromine atom or a methyl or phenoxy radical in the 2-position or with a methoxy radical in the 4-position, or in which A means a cis-vinylene radical and X means an unsubstituted phenyl radical.

Those where A means an ethylene radical and X means a phenyl radical which is substituted with a methyl radical in the 2-position or with a fluorine atom in the 4-position.

Special compounds produced according to the invention are described in the examples and the preferred compounds are those where A means an ethylene radical and X means a phenyl radical which is unsubstituted or which is substituted with a phenoxy radical in the 2-position, or A means a trans-vinylene radical and X means a phenyl radical which is unsubstituted or which is substituted with an ethoxy radical in the 2-position, and the salts thereof as indicated above. These preferred compounds are active in the RHL test (see later) at doses below 10 mg/kg.

A suitable pharmaceutically acceptable acid addition salt of the morpholine derivatives produced according to the invention is, e.g. a hydrochloride, hydrobromide, phosphate or sulfate, or a citrate, acetate, maleate or oxalate.

According to the invention, the morpholine derivative can be produced by methods which are known in and of themselves for the production of chemically analogous compounds, for example a method whereby X and A have the above meanings,

characterized by that

(a) the radical. R"<*>" in a compound with the formula: ;where R<1> is an alkanoyl or optionally substituted alkoxycarbonyl radical with up to 6 carbon atoms, an aroyl, α-arylalkyl or aryloxycarbonyl radical ~ with up to 11 carbon atoms or a cyano radical, is replaced by hydrogen, by hydrolysis with an acid or base, by reaction with zinc, by reaction with a complex metal hydride or by hydrogenolysis, (b) for the compounds where A is an ethylene radical, a compound of the formula is reduced: ;with hydrogen in the presence of a catalyst, (c) for the compounds where A is a vinylene radical, a compound with the formula is dehydrated: by means of toluene-p-sulfonic acid or methyltriphenoxyphosphonium iodide, (d) for those compounds where A is an ethylene radical, a compound of formula IV is reacted with hydrogen in the presence of a catalyst, (e) a compound of the formula ;where Z means a replaceable halogen atom or sulfonyloxy radical, is cyclized in the presence of a base, ;(f) a compound of the formula: ;;is reduced, ;(g) for those compounds where A is an ethylene radical, a compound of the formula ;;is desulfurized in the presence of a catalyst such as Raney nickel , ;(h) for the compounds where A is a trans-vinylene radical, a compound with the formula is isomerized: With a thiophenol in the presence of a catalyst or with an acid, (i) for the compounds where A is a vinylene radical, the elements hydrogen and halogen are removed from a compound of the formula: ;where Y is a halogen atom, by heating with a base, ;while a compound which is an optically active enantiomer is prepared ;by cleavage of the racemic compound of formula I in the usual manner e, or by using one of the methods (a) to (i) where the intermediate with formulas II, III, IV, V, VI, VII, VIII or IX is itself a split isomer. In method (a), when R is an alkanoyl, optionally substituted alkoxycarbonyl, aroyl or aryloxycarbonyl radical, e.g. respectively an acetyl, ethoxycarbonyl, benzoyl or phenoxycarbonyl radical, is replaced by hydrogen by hydrolysis with an acid or a base, e.g. "with hydrochloric or hydrobromic acid or sodium or potassium hydroxide, in a diluent or solvent, such as acetic acid, ethanol or water or a mixture of any two of these. When R"<*>" is an optionally substituted alkoxycarbonyl radical, e.g. an alkoxycarbonyl radical with at least 3 carbon atoms which is substituted on the 3-carbon atom of the alkyl group by at least one chlorine or bromine atom, e.g. when R''" is a 2,2,2-trichloroethoxycarbonyl radical , it can be replaced by hydrogen by reaction with zinc, e.g. with zinc in the presence of a dilute acid, e.g. acetic acid. When R is a cyano radical, it can be replaced by hydrogen by reaction with a complex metal hydride, e.g. lithium aluminum hydride, in a diluent or solvent such as diethyl ether or tetrahydrofuran. All of the above turnovers can be accelerated or completed by the application of heat, e.g.

by heating to the boiling point of the diluent or solvent.

When R is an α-arylalkyl radical, e.g. a benzyl radical, it can be replaced by hydrogen by hydrogenolysis. The hydrogenolysis can be carried out using hydrogen in the presence of a palladium-on-charcoal catalyst, at ambient temperature and atmospheric pressure in a diluent or solvent such as ethanol, and can be accelerated by the addition of an acidic catalyst, e.g. hydrochloric acid.

Processes (b) and (d) can be carried out using hydrogen in the presence of a palladium-on-charcoal catalyst at ambient temperature and atmospheric pressure in a diluent or solvent such as ethanol.

Process (c) can be carried out using toluene-p-sulfonic acid in a solvent such as toluene or xylene, the water formed during the reaction being removed azeotropically, or with methyltriphenoxy-phosphonium iodide in e.g. hexamethylphosphoric triamide as solvent.

In method (e), Z can for example be a chlorine

or bromine atom or a radical of the formula OS02R 2 in which R<2>

means a hydroxy radical or a lower alkyl or an aryl

radical, e.g. a methyl, ethyl, phenyl or p-tolyl radical.

The base used in the reaction can be an alkali or alkaline earth metal hydroxide, e.g. sodium, potassium or barium hydroxide. The reaction can be carried out in a diluent or solvent, for example water, an alcohol, such as methanol or ethanol, or an ether, for example diethyl ether, dimethoxyethane or tetrahydrofuran, and it can be carried out at ambient

temperature or at a temperature up to the boiling point of the diluent or solvent, e.g. a temperature of

-between 40 and 100°C.

Method (f) can be carried out with a complex metal

hydride, e.g. lithium aluminum hydride, in a diluent or solvent, such as diethyl ether or tetrahydrofuran,

and turnover can be accelerated or completed by the application of heat, e.g. by heating to the boiling point for dilution

the agent or the solvent.

Method (g) is carried out in the presence of a

catalyst, such as Raney nickel, e.g. in a diluent or solvent such as toluene or xylene.

Method (h) is carried out with a thiophenol,

such as thiophenol or 4-chlorothiophenol, in the presence of a catalyst,

such as azobis-isobutyronitrile, and in a diluent or solvent, such as toluene or xylene, or with an acid,

such as hydrochloric acid, in a solvent such as water, and it may be accelerated or completed by the application of heat, e.g. by heating to the boiling point of the diluent or solvent.

Method (i) is carried out by heating with a base,

e.g. 1,5-diazabicyclo[5.4.0]undec.-5-ene, in a diluent or solvent, such as dimethyl sulfoxide.

Where the structures of the starting material and the product permit, two of the above methods can be carried out simultaneously. Thus, by applying hydrogenation conditions, progress

ways (a) and (b) or (a) and (d) are carried out together.

The starting material "for use in the methods

(a), (b) and (h) where A is a vinylene radical, can be prepared as described in Example 1, by reacting 4-benzyl-2-(toluene-p-sulfonyloxymethyl)morpholine and lithium iodide to give 4-benzyl -2-iodomethylmorpholine. This compound is then reacted with triphenylphosphine to give 4-benzylmorpholin-2-ylmethyl-triphenylphosphonium iodide which is then reacted with a base to form the corresponding phosphorane. This intermediate is reacted in situ with an appropriately substituted benzaldehyde to give 4-benzyl-2-(3-substituted phenylvinyl)-morpholine as a mixture of cis and trans isomers. These isomers are, if necessary, separated by chromatography, or by fractional crystallization of an acid addition salt, and if necessary this N-benzyl derivative is used to form other N-substituted starting materials. Thus, reaction with an aryl or optionally substituted alkyl chloroformate gives the corresponding phenoxy- or alkoxy-carbonyl derivative, or reaction with cyanogen bromide gives the corresponding N-cyano derivative.

The starting material for use in processes (c) and (d) can be prepared, as described in Examples 17 and 18, by reacting 4-benzyl-2-(toluene-p-sulfonyloxymethyl)morpholine with sodium cyanide followed by reacting the resulting 4- benzyl-2-cyanomethylmorpholine with an aryl lithium or aryl Grignard. The resulting ketone is then reduced to the corresponding alcohol which is obtained as a mixture of diastereoisomers.

The starting material for use in method (e) where A is an ethylene radical, can be prepared, as described in example 13, by reacting a suitably substituted phenylpropionaldehyde with a mixture of trimethyloxosulfonium iodide and sodium hydride. The resulting epoxide is then reacted with 2-aminoethyl hydrogen sulfate. Alternatively, the starting material for use in method (e) where A is a vinylene radical, e.g. is prepared by reacting l-bromo-4-phenylbut-3-en-2-one with 2-aminoethyl hydrogen sulfate followed by reduction of the ketone group to the corresponding alcohol.

The starting material for use in method (f) can be prepared, as described in example 14, by reacting 1,2-epoxy-4-phenylbutane with benzylamine followed by reacting the product with chloroacetyl chloride. The N-benzyl-N-chloroacetyl derivative thus obtained is ring-closed to N-benzyl-morpholone with sodium methoxide and the benzyl group is then replaced with hydrogen by reaction with sodium in liquid ammonia.

The starting material for use in method (g) can be obtained, as described in example 19, by reacting a suitable 4-benzyl-2-phenacylmorpholine with cyanogen bromide to give the corresponding 4-cyano derivative which is then reacted with ethanedithiol. The cyano group in the resulting dithioketal is then replaced with hydrogen by reduction with lithium aluminum hydride.

The starting material for use in method (i)

can e.g. is produced by direct halogenation of the corresponding derivative where A is an ethylene radical.

The compounds produced according to the invention are psychotropic agents, that is to say, they have the ability to restore the normal state in the case of an abnormal mental state in warm-blooded animals. E.g. the compounds according to the invention exhibit antidepressant and sedative activity. By antidepressant activity we mean the clinical effect produced by tricyclic antidepressants, such as imipramine, when these are used to treat the clinical syndrome known as depression.

Antidepressant activity is shown by reversal of reserpine-induced hypothermia in mice, a standard test (Askew, Life Sciences, 1963, 2, 725) used in industry to determine the relative quantitative antidepressant activity of a series of chemically related compounds.

Sedative activity is shown by reduction of the spontaneous activity in mice, as measured by photobeam interruptions, a standard test (Riley and Spiks, J. Pharm. Pharmacol., 1958, 10, 662-663) used in industry to assess sedatives activity, and compounds active in this test are therefore useful as sedatives, e.g., to produce a calming effect on

irritable and aggressive animals.

All the compounds of which examples are given in this description are active in at least one of the above-mentioned tests, although not all compounds are active in both tests. In addition, analgesic activity is widespread throughout the series.

Reversal of reserpine-induced hypothermia, known as the RHL test, is performed as follows: Mice are kept in a room at a constantly maintained temperature of 21 h 1°C. Reserpine is given to each participant in groups of 4 mice. (2 mg base per kg body weight, given subcutaneously as the acetate). 17 hours later, the esophageal temperature (TQ) of each mouse is noted down using an orally inserted probe connected to an electrical thermometer calibrated in degrees Celsius that can be read every 0.1°C. Immediately after the temperature measurement, the mice are dosed orally with the test compound, or with imipramine, each mouse in a group of 4 receiving the same substance, and the esophageal temperatures are again noted down after 4 hours (T^). The test compound is given in serial dilutions, e.g. 100, 30, 10, 3, 1, 0.3 and 0.1 mg/kg. Imipramine is used for comparison. In a large number of tests, it has been found that 3 mg/kg of imipramine produces an average rise in temperature in a reserpine-treated mouse of 3°C. At 1 mg/kg it produces an average rise of 1.7°C. A test compound which, at a given dose level, produces an increase in temperature equal to or greater than that produced by 1 mg/kg imipramine, given to different sets of mice on the same day, is judged to be "active" at that dose .

The measurement of reduction of spontaneous activity for mice is carried out in the following way: Groups of 6 mice are orally given the test compound and 45 minutes later they are placed individually in cages equipped with a central, horizontal scanning photobeam. The number of beam interruptions in the first 45 minutes is noted down and the percentage inhibition of movement in relation to comparison animals is calculated. The compound is considered active if the amount of movement for the dosed animals is reduced by more than one-third compared to the control animals.

All compounds exemplified in this specification are active in at least one of these two tests at a dose of less than or equal to 100 mg/kg of free base, while at the same dose showing no obvious signs of toxicity.

The compound 2-[3-(2-phenoxyphenyl)ethyl]morpholine has an oral LD^q in mice of 550 mg/kg.

The compounds can be used in pharmaceutical compositions which comprise as active ingredient a morpholine derivative prepared according to inventions L, together with a pharmaceutically acceptable carrier or diluent.

Biological results

: The values in brackets are for the corresponding compounds where

A is -O-CH2-.

The invention is illustrated by the following examples:

Example 1

A solution of sodium methylsulfinylmethide is prepared

in the usual manner from an 80% mineral oil dispersion of sodium hydride (4.36 g) and dimethyl sulfoxide (350 ml). Water (2.1 ml) is added and the mixture is stirred and heated at 60°C while a solution of 4-phenoxycarbonyl-2-[3-(4-methoxyphenyl)-cis-vinyl]morpholine (6.1 g)

in dimethyl sulfoxide (20 mL) is added. The mixture is stirred and heated at 50-60°C for 3 hours. The mixture is cooled, diluted with water (500 mL) and brine (500 mL), and extracted with ethyl acetate (3 x 300 mL). The combined extracts are washed with water (3 x 200 ml), dried over anhydrous magnesium sulfate and the solvent is removed from the filtered solution by evaporation under reduced pressure. The residue is converted to its maleate salt which is crystallized from a mixture of ethyl acetate and methanol to give 2-13-(4-methoxy-phenyl)-cis-vinyl]morphoTin hydrogen maleate, m.p. T58-159°C.

The 4-phenoxycarbonyl-2-[3-(4-methoxyphenyl)-cis-vinyl]morpholine used as starting material can be obtained in the following way: A mixture of 4-benzyl-2-(toluene-p-sulfonyloxymethyl)-morpholine (120 g.), lithium iodide monohydrate (100 g) and dry dimethylformamide (800 ml) are stirred and heated at 100-110°C in an atmosphere of nitrogen for 2 hours. The mixture is cooled, diluted with water (1.5 1) and extracted with petroleum ether (b.p. 60-80°C)

(3 x 500 ml). The combined extracts are dried and the solvent is removed. 4-benzyl-2-iodomethyl-morpholine is thus obtained, m.p. 42-45°C, which is not purified further.

A solution of 4-benzyl-2-iodomethylmorpholine (100.4 g)

and triphenylphosphine (82.5 g) in dry xylene (1 liter) is stirred and refluxed for 24 hours. The mixture is cooled and filtered and the solid is recrystallized from methanol.

4-benzylmorpholin-2-ylmethyl-triphenyl-phosphonium iodide is thus obtained, m.p. 271-272°C.

A mixture of 4-methoxybenzaldehyde (4.08 g) and 4-benzyl-morpholin-2-ylmethyl-triphenyl-phosphonium iodide (17.37 g) in dry dimethylformamide (500 ml) is stirred at ambient temperature in an atmosphere of nitrogen. An 80% mineral oil dispersion of sodium hydride (0.9 g) is added and the mixture is stirred and the temperature is slowly raised to 110°C over 1 hour. The mixture is stirred at 110°C for 12 hours, then cooled, diluted with water (500 ml) and extracted with ethyl acetate (3 x 500 ml). The ethyl acetate extracts are combined and washed with water (3 x 300 mL) and dried over anhydrous magnesium sulfate, and the solvent is removed in the usual manner. A rubber is thus obtained which consists of a mixture of the cis- and trans-ethylene derivatives and triphenyl-phosphine oxide. This mixture dissolved in toluene (30 ml) is chromatographed on magnesium silicate (500 ml). Elution with toluene (2 1) gives 4-benzyl-2-[3-(4-methoxyphenyl)-cis-vinyl]morpholine which gives a hydrogen oxalate hemihydrate, m.p. 120-122°C after crystallization from a mixture of methanol and ethyl acetate. Further elution with toluene (1 liter) gives 4-benzyl-2-[3-(4-methoxyphenyl)-trans-vinyl]morpholine which gives a hydrogen oxalate, m.p. 191-192<Q>C, from ethyl acetate and methanol.

To a solution of 4-benzyl-2-[3-(4-methoxyphenyl)-cis-vinyl]morpholine (6.0 g) in dry methylene chloride (150 ml) is added phenyl chloroformate (2.74 ml). The mixture is stirred at ambient temperature for 4 hours. The solution is washed with 2N hydrochloric acid solution (50 ml), water (50 ml) and saturated sodium bicarbonate solution (50 ml) and is dried, and the solvent is removed by evaporation. 4-phenoxycarbonyl-2-[3-(4-methoxyphenyl)-cis-vinyl]morpholine is thus obtained as an oil which is not further purified.

Example 2

A solution of 4-cyano-2-[3-(4-methoxyphenyl)-trans-vinyl]morpholine in tetrahydrofuran (10 mL) is added dropwise to a stirred suspension of lithium aluminum hydride (0.25 g) in dry ether (60 mL ). The mixture is stirred at ambient temperature for 3 hours. The mixture is cooled in an ice bath and water (0.25 ml), 2N sodium hydroxide solution (0.25 ml) and water (0.75 ml) are successively added. The mixture is stirred for 15 minutes, filtered

and the filtrate is evaporated under reduced pressure. The residue is converted to the maleate salt which is crystallized from a mixture of methanol and ethyl acetate to give 2-[3_(4-methoxyphenyl)-trans-vinyl]morpholine maleate, m.p. 153-154°C.

The 4-cyano-2-[3-(4-methoxy-phenyl)-trans-vinyl]morpholine used as starting material can be prepared in the following way: To a solution of 4-benzyl-2-[3-(4-methoxyphenyl) -trans-vinyl]morpholine (1.03 g) in dry methylene chloride (100 ml) is added cyanogen bromide (0.39 g). The mixture is stirred at ambient temperature for 12 hours and then the solvent is removed under reduced pressure. The residue is dissolved in ethyl acetate (100 ml) and the organic solution is washed successively with

2n hydrochloric acid solution (50 ml), water (50 ml) and saturated sodium chloride solution (50 ml) and is dried over anhydrous magnesium sulfate. Removal of the solvent gives 4-cyano-2-[3~(4-methoxy-

phenyl)-trans-vinyljmorpholine.

Example 3

The procedure described in Example 1 is repeated using an appropriately substituted 4-phenoxycarbonyl derivative as starting material in place of 4-phenoxycarbonyl-2-[3-(4-methoxyphenyl)-cis-vinyl]morpholine, and the following compounds are thus obtained:

The starting materials for the above compounds can be prepared by repeating the procedure described in the fourth part of Example 1, using a suitable aldehyde as starting material instead of 4-methoxybenzaldehyde. The following compounds are thus obtained:

These 4-benzyl derivatives are then reacted with phenyl chloroformate as described in the fifth part of example 1. The 4-phenoxycarbonyl derivatives thus obtained are used without purification.

Example 4

A solution of 4-benzyl^2-[3-(2-ethoxyphenyl)-cis-vinyl]-morpholine hydrogen oxalate (1.4 g) in ethanol (50 ml) is hydrogenated at ambient temperature and pressure over a catalyst of 30 % palladium-on-charcoal (0.3 g) until no more hydrogen is absorbed. The mixture is filtered and the filtrate is evaporated under reduced pressure. The residue is crystallized from a mixture of methanol and ether to give 2-[3-(2-ethoxyphenyl)ethyl]-morpholine hydrogen oxalate, m.p. 119-121°C.

The 4-benzyl-2-[3"(2-ethoxyphenyl)-cis-vinyl]morpholine hydrogen oxalate used as starting material can be obtained by repeating the procedure described in the fourth part of example 1, using 2-ethoxybenzaldehyde instead for 4-methoxybenzaldehyde as starting material The product has a m.p. of 156-158°C after recrystallization from ethanol/ether.

Example 5

The procedure described in Example 4 ..is repeated using a suitable 4-benzyl derivative as starting material. The following compounds are thus obtained as their hydrogen oxalates:

Example 6

A solution of 2-[3-(4-methoxyphenyl)-cis-vinyl]morpholine (1.4 g) in ethanol (40 mL) and saturated ethanolic hydrochloric acid (0.5 mL) is hydrogenated at ambient temperature and pressure over a 5% palladium-on-charcoal catalyst (0.5 g) until no more hydrogen is absorbed. The mixture is filtered and the filtrate is evaporated under reduced pressure. The remaining oil is made basic with 2N sodium hydroxide solution and the product is obtained in the conventional manner by extraction with ethyl acetate. The free base is converted to its maleate salt and recrystallized from a mixture of methanol and ethyl acetate. 2-[3-(4-methoxyphenyl)ethyl]morpholine hydrogen maleate is thus obtained, m.p. 152-153°C.

Example 7

The procedure described in example 6 is repeated using a suitable 2-cis-vinylmorpholine as starting material, and the following compounds are thus obtained after recrystallization from methanol/ethyl acetate:

The 2-[3-(4-chlorophenyl)-cis-vinylmorpholine hydrogen maleate used as starting material can be obtained by repeating the procedure described in the fourth part of example 1, using 4-chlorobenzaldehyde as starting material instead of 4-methoxybenzaldehyde . 4-benzyl-2-[3_(4-chlorophenyl)-cis-vinyl]morpholine hydrogen oxalate is thus obtained, m.p. 181-182 after recrystallization from methanol/ethyl acetate.

This product is reacted with phenyl chloroformate according to the procedure described in the fifth part of Example 1, and the product, which is not purified, is subjected to the procedure described in the first part of Example 1 to give 2-[3-(4- chlorophenyl)-cis-vinyl]morpholine hydrogen maleate, m.p. 129-130°C after recrystallization from methanol/ethyl acetate/ether.

Example 8

The procedure described in example 1 is repeated using 4-phenoxycarbonyl-2-[3-(2-chlorophenyl)-trans-vinyl]-morpholine as starting material, and 2 — [3— (2 — chlorophenyl)-trans is thus obtained -vinyl]morpholine hydrogen maleate, m.p. 145-146°C after recrystallization from methanol/ethyl acetate.

The 4-phenoxycarbonyl-2-[3-(2-chlorophenyl)-trans-vinyl]morpholine used as starting material can be prepared by repeating the procedure described in the fourth part of example 1, using 2-chlorobenzaldehyde as starting material. 4-benzyl-2-[3-(2-chlorophenyl)-trans-vinyl]morpholine hydrogen oxalate is thus obtained, m.p. 175-176°C after recrystallization from methanol/ethyl acetate. The corresponding 4-phenoxycarbonyl derivative is then obtained by repeating the procedure described in the fifth part of example 1, and is used without further purification.

Example 9

The procedure described in Example 2 is repeated using an appropriately substituted 4-cyano derivative as starting material in place of 4-cyano-2-[3-(4-methoxyphenyl)-trans-vinyl]-morpholine, and the following compounds are obtained thus obtained after recrystallization from methanol/ethyl acetate:

The starting materials for the above compounds can be prepared (a) by repeating the procedure described in the fourth part of Example 1 using a suitable aldehyde as starting material instead of 4-methoxybenzaldehyde. The following compounds are thus obtained as their hydrogen oxalates after recrystallization from methanol/ethyl acetate:

or (b) by a method exemplified as follows: A solution of 4-benzy 1-2-((J-phenyl-cis-vinyl)-morpholine (0.84 g), thiophenol (0.89 g) and azobisisobutyronitrile (0.01 g)

in dry toluene (10 ml) is heated at 70°C for 8 hours. The mixture is cooled and diluted with ether (50 mL) and the organic solution is extracted with 5% w/v aqueous sodium hydroxide solution (3 x 20 mL). The organic solution is dried and the solvent is removed under reduced pressure to give an oil consisting of 4-benzyl-2-(0-phenyl-trans-vinyl)morpholine which is contaminated with a small amount of the cis-isomer. The trans compound is purified by conversion to its oxalate salt by conventional means and is crystallized from methanol/ethyl acetate. 4-benzyl-2-(f-phenyl-trans-vinyl)morpholine hydrogen oxalate is thus obtained, m.p. 171-173°C (dec.). By using an appropriately substituted cis compound in place of 4-benzyl-2-(p-phenyl-cis-vinyl)morpholine and

repeating the procedure described immediately above, the following compounds are obtained:

or (c) by a method exemplified as follows:

A solution of 4-benzyl-2-(Ø-phenyl-cis-vinyl)morpholine (0.75 g) in dry dimethylformamide (50 ml) is stirred and a 30% w/w mineral oil dispersion of sodium hydride ( 0.82g). The mixture is slowly heated to 110°C in an atmosphere of nitrogen and the temperature is maintained at 110°C for 2 hours. The mixture is cooled and diluted with water and the product is obtained by extraction with ethyl acetate. An oil is thus obtained which consists of 4-benzyl-2-[p-phenyl-trans-vinyl]morpholine contaminated with a small amount of 4-benzyl-2-(3-phenylethylidene)-morpholine. This oil is dissolved in toluene (5 ml) and chromatographed on magnesium silicate (50 g). Elution with toluene (200 ml) gives 4-benzyl-2-[3-phenylethylidene]morpholine which is discarded. Further elution with toluene containing 5% v/v ethyl acetate gives 4-benzyl-2-[3-phenyl-trans-vinyl]morpholine which is used without further purification.

By using an appropriately substituted cis compound

instead of 4-benzyl-2-[3-phenyl-cis-vinyl]morpholine, in the method described immediately above, 4-benzyl-2-[3-(2-methylphenyl)-trans-vinyl]morpholine is obtained and 4- benzyl-2-[3-(2-phenoxyphenyl)-trans-vinyl]morpholine which is used without further purification.

These 4-benzyl derivatives are then reacted with cyanogen bromide as described in the second part of example 2. The 4-cyano derivatives thus obtained are used without purification.

Example 10

The procedure described in Example 2 is repeated using 4-cyano-2-(3-phenylethyl)morpholine as starting material instead of 4-cyano-2-[3-(4-methoxyphenyl)-trans-vinyl]morpholine, and the 2-(3-phenylethyl)morpholine is thus obtained as its hydrogen oxalate salt, syrup. 151-152°C. after crystallization from methanol/ethyl acetate.

The 4-cyano-2-(3-phenylethyl)-morpholine used as starting material can be obtained in the following way: A solution of 4-benzyl-2-(3-phenyl-cis-vinyl)-morpholine hydrogen oxalate hemihydrate ( 0.5 g) in absolute ethanol (50 ml)

is hydrogenated at ambient temperature and pressure over a platinum catalyst obtained by pre-hydrogenation of platinum oxide (0.1 g) until an equivalent (32 ml) of hydrogen is absorbed. The mixture is filtered and the solvent is removed from the filtrate. The residue is crystallized from methanol/ethyl acetate and 4-benzyl-2-(3-phenylethyl)morpholine hydrogen oxalate is thus obtained, m.p. 168-169°C.

This compound is then reacted with cyanogen bromide using the method described in the second part of example 2. 4-cyano-2-(3-phenylethyl)morpholine is thus obtained which is used without further purification.

Example 11

To a solution of 4-(2,2,2-trichloroethoxycarbonyl)-2-[3-(2-phenoxyphenyl)-cis-vinyl]morpholine (0.34 g) in acetic acid

(20 ml) zinc dust (0.4 g) is added. The mixture is stirred

at ambient temperature for 12 hours and is then basified with 2N sodium hydroxide solution and the product is extracted with ethyl acetate (3 x 50 ml). The ethyl acetate is removed from the dried combined extracts by evaporation, and the residue is converted to its maleate salt by recrystallization from methanol/ethyl acetate to give 2-[3"(2-phenoxyphenyl)-cis-vinyl]morpholine hydrogen maleate, m .p. 148-149°C.

The 4-(2,2,2-trichloroethoxycarbonyl)-2-[3-(2-phenoxyphenyl)-cis-vinyl]morpholine used as starting material can be obtained by repeating the procedure described in the last part of example 1, by using equivalent amounts of 4-benzyl-2-[3-(2-phenoxy-phenyl)-cis-vinyl]morpholine and 2,2,2-trichloroethoxycarbonyl chloride instead of 4-benzyl-2-[3-(4 -methoxyphenyl)-cis-vinyl]-morpholine and phenyl chloroformate. The product is obtained as an oil which is not further purified.

Example 12

The procedure described in Example 6 is repeated using an equivalent amount of 2-[3-(4-fluorophenyl)-cis-vinyl]morpholine or 2-[3-(4-fluorophenyl)-trans-vinyl]morpholine as starting material instead of 2-[3-(4-methoxyphenyl)-cis-vinyl]-morpholine, and 2-[3-(4-fluorophenyl)ethyl]morpholine hydrogen maleate is thus obtained, m.p. 141-142°c after recrystallization from methanol/ethyl acetate.

Example 13

A mixture of 1,2-epoxy-4-phenylbutane (1.48 g) and 2-aminoethyl hydrogen sulfate (7.05 g) in methanol (7.5 mL) and sodium hydroxide solution (18 n, 2.8 ml) is stirred at ambient temperature for 2 hours. The 2-(2-hydroxy-4-phenylbutyl)aminoethyl hydrogen sulfate formed as an intermediate is not isolated, but is cyclized in situ in the following manner: A further portion of sodium hydroxide solution (18 n, 5.6 ml) is added. and the mixture is stirred and heated at 60°C for 24 hours. Water (100 mL) is added and the mixture is extracted with ethyl acetate (3 x 50 mL). The combined ethyl acetate extracts are self-extracted with hydrochloric acid solution (2n, 3 x 50 ml) and the organic solution is discarded. The acid extracts are combined and made basic with 18N sodium hydroxide solution. The basic solution is extracted with ethyl acetate (3 x 50 mL) and the combined organic extracts are dried and the solvent is removed under reduced pressure. The residue is converted to its oxalate salt which is crystallized from methanol/ethyl acetate to give 2-(3-phenylethyl)-morpholine hydrogen oxalate, m.p. 151-152°C.

The 1,2-epoxy-4-phenylbutane used as starting material can be obtained in the following way: A solution of trimethyloxosulfonium iodide (2.64 g) in dry dimethyl sulfoxide (50 ml) is stirred at 50-60°C in an atmosphere of nitrogen and an 80% w/w mineral oil dispersion of sodium hydride (0.36 g) is added. Stirring and heating are continued until the solution is clear and no more hydrogen is evolved. A solution of 3-phenylpropionaldehyde (1.4 g) in dry dimethylsulfoxide (10 ml) is added and the mixture is stirred at 50-60°C in a nitrogen atmosphere for 3 hours. The mixture is cooled and diluted with water (200 ml) and the product is obtained by extraction with ethyl acetate (3 x 80 ml). Removal of the solvent from the combined extracts gives 1,2-epoxy-4-phenylbutane as an oil which is not further purified.

Example 14

A solution of 2-(3-phenylethyl)morpholin-5-one (430 mg) in dry terahydrofuran (4 ml) is added to a stirred suspension of lithium aluminum hydride (200 mg) in dry ether (20 ml) at such a rate that the mixture undergoes a slight reflux. After the addition is complete, the mixture is stirred and refluxed for 2 hours, then it is cooled and water (0.2 ml), sodium hydroxide solution (2n, 0.2 ml) and water (0.6 ml) are successively added and the stirring will continue for 15 minutes. The mixture is filtered and the filtrate is evaporated under reduced pressure to

give 2-(3-phenylethyl)morpholine as an oil which can be converted into its hydrogen-oxalate salt, m.p. 151-152, or its hydrogen maleate salt, m.p. 120-122 after recrystallization from methanol/ethyl acetate.

The 2-(3_phenylethyl)morpholin-5-one used as starting material can be obtained in the following way: A mixture of 1,2-epoxy-4-phenylbutane (5.91 g) and benzylamine (10 ml) is stirred and heated at 140°C for 18 hours. Excess benzylamine is removed by distillation under reduced pressure (20 mm) (bath temperature 110°C) The remaining oil is converted to its hydrogen oxalate salt which is crystallized from methanol/ethyl acetate to give 1-benzylamino-4-phenylbutane-2 -ol-hydrogen-oxalate, m.p. 196°C.

This product is back-converted to the free base

by conventional means and the free base (3.7 g) is dissolved in dry methylene chloride (37 ml) and triethylamine (2 ml) is added. The mixture is stirred and cooled to 0°C and within 15 minutes a solution of chloroacetyl chloride is added dropwise

(1.64 g) in dry methylene chloride. (10ml). The mixture is stirred at ambient temperature for 2 hours and then washed with hydrochloric acid solution (2n, 2 x 20 ml) and water (20 ml) and dried and

the solvent is removed under reduced pressure. 1-N-chloroacetyl-benzylamiho-4-phenylbutan-2-ol is thus obtained, which is not further purified.

This product is dissolved in methanol (50 ml) and a solution of sodium methoxide prepared from sodium metal (0.33 g) and methanol (10 ml) is added. The mixture is stirred and refluxed for 18 hours. The mixture is cooled and filtered and the filtrate is evaporated under reduced pressure. The residue is dissolved in ethyl acetate (50 ml) and the solution is washed successively with water (20 ml), hydrochloric acid solution (2n, 20 ml), water (20 ml) and saturated saline (20 ml). The ethyl acetate solution is dried and the solvent is removed under reduced pressure to give 4-benzyl-2-(3-phenylethyl)morpholin-5-one which is not further purified.

A solution of this compound (2.2 g) in dry tetrahydrofuran (10 ml) is added dropwise over 10 minutes to a stirred solution of sodium (0.332 g) in liquid ammonia (50 ml). After the addition is complete, sodium (0.1 g) is added and the mixture is stirred for 20 minutes. Ammonium chloride (1 g) is added and the ammonia is allowed to evaporate. The residue is partitioned between water (50 ml) and ethyl acetate (50 ml) and the ethyl acetate layer is separated and dried and the solvent is removed under reduced pressure. The residue is crystallized from diethyl ether to give 2-(3-phenylethyl)morpholin-5-one, m.p. 100-102°c.

Example 15

A solution of 2-(3-phenyl-cis-vinyl)morpholine (0.189 g), thiophenol (0.1 g) and azobisisobutyronitrile (0.03 g) in dry toluene (30 ml) is stirred and heated at 110°C for 18 hours. The mixture is cooled and diluted with ether (50 mL) and the organic solution is washed successively with sodium hydroxide solution (2n, 3 x 20 mL) and water (20 mL) and dried, and the organic solvent is removed under reduced pressure. 2-(3-phenyl-trans-vinyl)morpholine is thus obtained which is converted to its hydrogen maleate salt, m.p. 123-124°C after crystallization from methanol/ethyl acetate.

The same product can be obtained from the same starting material by repeating the above procedure using 4-chlorothiophenol (0.35 g) instead of thiophenol and heating for 2 hours.

Example 16

A solution of 2-[3-(4-methoxyphenyl)-cis-vinyl]-morpholine (0.219 g), thiophenol (0.3 g) and azobisisobutyronitrile (0.03 g) in dry toluene (3 ml) was stirred stirred and heated at 70-80°C for 12 hours. The product is obtained as described in example 15 and thus 2-[3-(4-methoxyphenyl)-trans-vinyl]morpholine-hydrogen-maleate/ m.p. 153-154°C after recrystallization from methanol/ethyl acetate.

Example 17

One. solution of 4-benz<y>l-2-phenac<y>-lmorpholine (0.95 g) 9 ethanol (18 ml) and perchloric acid (1 drop) is hydrogenated at ambient temperature and pressure over a 30% wt. /weight of palladium-on-trek':ll catalyst (0.1 g) until no more hydrogen is absorbed. The mixture is heated to reflux, filtered through diatomaceous earth and the filtrate is evaporated under reduced pressure. The residue is dissolved in water, basified with 2N sodium hydroxide solution and extracted with ether (3 x 10 ml). The combined ether extracts are washed with saline, dried over magnesium sulfate and then evaporated in vacuo. The free base is converted to its oxalate salt and recrystallized from a mixture of methanol and ethyl acetate to give 2-[3-phenylethyl]morpholine hydrogen oxalate, m.p. 151-153°C.

The 4-benzyl-2-phenacyl-morpholine used as starting material can be obtained in the following way: A mixture of finely ground sodium cyanide (39.6 g) and 4-benzyl-2-(toluene-p-sulfonyloxymethyl)morpholine (144.4 g) ) in dimethylsulfoxide (600 ml) is stirred and heated at 60-65°C for 3.5 hours. The mixture is cooled, diluted with water (6 L) and extracted with ether (3 x 2 L). The ether extracts are combined and washed with salt solution (2x1 liter) and dried over anhydrous magnesium sulfate and the solvent is removed by evaporation in vacuo. The residue is recrystallized from petroleum ether (b.p. 40-60°C) to give 4-benzyl-2-cyanomethyl-morpholine, m.p. 62°C.

A phenyllithium solution is prepared by dropwise addition of a solution of dry bromobenzene (26.25 ml) in sodium-dried ether (125 ml) to a mechanically stirred mixture of small pieces of lithium (3.5 g) in sodium-dried ether (125 mL) in an argon atmosphere and at such a rate that a slight reflux is maintained. After the addition of the bromobenzene solution is complete, a further portion of dry bromobenzene (5 ml) is added and the stirred mixture is heated under reflux for 30 minutes. The reaction mixture is cooled to -20°C (acetone/solid (X^) and a solution of 4-benzyl-2-cyanomethyl-morpholine (27.0 g) in sodium-dried ether (135 ml) is added dropwise with stirring and at such a rate as to maintain a temperature of -20 to -15° C. The mixture is stirred at -15° C. for 15 minutes, is added with stirring to an ice-cold hydrochloric acid solution (ln, 2 liters) and is stirred in 15 minutes during which time a solid crystallizes from the solution. The product is filtered, washed with a small volume of water, then with ether, and then dried in vacuo. Recrystallization from isopropanol gives 4-benzyl-2- phenacetylmorpholine hydrochloride, mp 184-186°C.

Example 18

A mixture of 2-(3-hydroxy-3-phenylethyl)morpholine (3.1 g) and methyltriphenoxyphosphonium iodide (38 g) in hexamethylphosphoric acid triamide (120 ml) is stirred and heated at 75°C in a nitrogen -atmosphere for 1 hour. The cooled mixture is diluted with water (1200 mL), basified with 18N sodium hydroxide solution and extracted with ethyl acetate (3 x 250 mL). The combined ethyl acetate extracts are washed with 50% volume/volume aqueous salt solution (2 x 200 ml), dried over anhydrous sodium sulfate and evaporated in vacuo. The remaining yellow oil is dissolved in ether and is added to ethereal oxalic acid (one molar equivalent) to give a sticky solid. The ether is decanted off and fresh ether is added and it is decanted and the residue is rubbed with hot acetone. Thus 2-(3-phenyl-trans-vinyl)morpholine hydrogen oxalate is obtained, m.p. 173-176°C

by recrystallization from methanol. The hydrogen oxalate can be converted to the free base and then to hydrogen maleate, m.p. 122-123°C by recrystallization from ethanol/ethyl acetate.

The 2-(3-hydroxy-3-phenyl-ethyl)morpholine used as starting material can be obtained in the following way: A solution of 4-benzyl-2-phenacylmorpholine (9.2 g) in absolute ethanol (200 ml) is hydrogenated at ambient temperature and press over a 5% w/w palladium-on-charcoal catalyst (1.0 g). After 3 days, a further 5% w/w palladium-on-charcoal catalyst (0.3 g) is added and dehydrogenated for a further 24 hours. The mixture is heated to reflux, filtered through diatomaceous earth and the filtrate evaporated in vacuo. Thus 2-(3-hydroxy-3-phenylethyl)-morpholine is obtained, which is used without further purification.

Example 19

A mixture of 2-(2-phenyl-[1,3]-dithiol-2-ylmethyl)morpholine

(0.5 g) and Raney nickel (4.0 g) in dry toluene (50 ml) is stirred at 15-20°C for 30 minutes. The mixture is filtered through diatomaceous earth and the residue is washed thoroughly with toluene. The toluene solution is evaporated in vacuo and the remaining gum is dissolved in ether and added to excess ethereal oxalic acid solution. Thus 2-(3-phenylethyl)morpholine hydrogen oxalate is obtained, m.p. 151-153°C by recrystallization from methanol/ethyl acetate.

The 2-(2-phenyl-[1,3]-dithiol-2-ylmethyl)-morpholine used as starting material can be obtained in the following way:

A solution of 4-benzyl-2-phenacylmorpholine (18.6 g)

and cyanogen bromide (8.2 g) in methylene chloride (186 mL) is stirred at ambient temperature overnight. The reaction solution is diluted with methylene chloride (700 mL) and is washed with aqueous HCl (2n, 125 mL) and water (2 x 125 mL), and is dried over anhydrous magnesium sulfate and the solvent is removed in vacuo. The residue is dissolved in minimal toluene and subjected to chromatography on magnesium silicate (700 g), and is eluted sequentially with toluene, 25% v/v chloroform/toluene,

50% v/v chloroform/toluene, chloroform and 50% v/v ethyl acetate/chloroform..The toluene fractions are discarded and the remainder is combined and evaporated in vacuo. Thus 4-cyano-2-phenacylmorpholine is obtained, m.p. 76-77°C by recrystallization from isopropanol.

A mechanically stirred mixture of 4-cyano-2-phenacyl-morpholine

(12.2 g), ethane-dithiol (5.3 mL) and sodium-dried benzene (36 mL)

is saturated with dry hydrogen chloride gas and is stirred at ambient temperature for 6 hours. The reaction mixture is diluted with water (50 ml), basified with 2N sodium hydroxide solution and diluted with petroleum ether (b.p. 60-80°C,

350 ml). The cooled suspension is filtered, the remaining solid is washed with water and thus 4-cyano-2-(2-phenyl-[1,3]-dithiol-2-ylmethyl)-morpholine is obtained, m.p. 110-111°C by recrystallization from absolute ethanol.

A solution of 4-cyano-2-(2-phenyl-[1,3]-dithiol-2-yl-methyl)morpholine (9.0 g) in dry tetrahydrofuran (180 ml) is added dropwise to a stirred suspension of lithium aluminum hydride (1.14 g)

in dry tetrahydrofuran (90 ml) under a nitrogen atmosphere and by cooling at 0-5°C. The mixture is stirred at 0-5°C for 1½ hours and is then treated successively with water (1.14 mL), sodium hydroxide solution (2N, 1.14 mL) and water (3.42 mL). The mixture is stirred at 0-5°C for 15 minutes and then filtered through diatomaceous earth and the residue is washed well with tetrahydrofuran. The tetrahydrofuran solution is evaporated in vacuo and the residue is heated with HCl solution (2n, 45 mL) on a steam bath for 30 minutes. The cooled solution is diluted with water (45 ml) and basified with ammonium hydroxide solution (m.p. 0.88) and extracted with ether (3 x 100 ml). The combined ether extracts are washed with water, dried over anhydrous magnesium sulfate and filtered, and the filtrate is added to ethereal oxalic acid solution. The salt thus obtained is purified by recrystallization from dimethylformamide/methanol and converted to its free base by suspension in chloroform, made basic with ammonium hydroxide solution (s.g. 0.88) and washed with water. The aqueous layer is extracted with chloroform (2 x 50 ml), the combined chloroform extracts are washed with water (2 x 50 ml) and dried over anhydrous potassium carbonate and the solvent is removed in vacuo. Thus 2-(2-phenyl-[1,3]-dithiol-2-ylmethyl)-morpholine is obtained, m.p. 86-88°C by recrystallization from toluene/petroleum ether (b.p. 60-80°C).

Example 20

A mixture of 2-(3-hydroxy-p-phenylethyl)morpholine (2.3 g) and toluene-p-sulfonic acid (2.4 g) in sodium-dried toluene (50 ml)

is heated at reflux for 2 hours with stirring in a nitrogen atmosphere under a Dean and Stark water separator. On cooling, the mixture gives 2-(3-phenyl-trans-vinyl)-morpholine-toluene-p-sulfonate, m.p. 170.5-172.5°C by recrystallization from absolute ethanol. The toluene p-sulfonate can be converted to the free base and then to the hydrogen maleate, m.p. 122-124°C by recrystallization from ethanol/ethyl acetate.

Example 21

A solution of 2-(3-phenyl-cis-vinyl)morpholine hydrogen maleate (0.2 g) in hydrochloric acid (lin, 10 ml) is heated at 90-100°C

for 30 minutes. The mixture is cooled, diluted with water (50 ml),

g-jort basic by addition of ammonia solution and extracted with ethyl acetate (3 x 30 ml). The ethyl acetate extracts are combined and dried over anhydrous magnesium sulfate and the solvent is removed under reduced pressure. Thus 2-(3-phenyl-trans-vinyl) morpholine is obtained, characterized as the hydrogen maleate,

sm.p. 123-124°C by recrystallization from methanol/ethyl acetate.

Example 22

A solution of 2-(3-hydroxy-3-phenylethyl)morpholine hydrochloride (JL g). i. ethanol. (30 mL) and 60% w/v aqueous perchloric acid solution (2 drops) is hydrogenated at ambient temperature and pressure over a 30% w/w palladium-on-charcoal catalyst (0.1 g) until no more hydrogen is absorbed. The mixture is filtered through diatomaceous earth and the filtrate is evaporated in vacuo. The residue is dissolved in water (20 ml), basified with aqueous sodium hydroxide solution (2n) and extracted with ether (3 x 20 ml). The combined ether extracts are washed with brine (1 x 25 ml), dried over anhydrous magnesium sulfate, concentrated in vacuo and added to an ethereal solution of oxalic acid to give 2-(3-phenylethyl-morpholine-hydrogen-oxalate, m.p. p. 151-152°C by recrystallization from methanol/ethyl acetate.

Claims (1)

Analogy method for the preparation of pharmacological active morpholine derivatives of the general formula where A means an ethylene- -K-CI^CF^-) or • vinylene radical (-GH=CH-) and X means a phenyl radical which is optionally substituted by one or two substituents selected from halogen atoms, alkyl and alkoxy radicals with 1 to 6 carbon atoms and phenoxy radicals with 6 to 10 carbon atoms, the phenoxy radicals themselves possibly being sub- substituted with one or two substituents selected from halogen atoms and alkyl radicals with 1 to 4 carbon atoms, and the pharmaceutically acceptable acid addition salts thereof, characterized in that (a) the radical R"<1>" in a compound with the formula where R"1" is an alkanoyl or optionally substituted alkoxycarbonyl radical with up to 6 carbon atoms, an aroyl, α-arylalkyl or aryloxycarbonyl radical with up to 11 carbon atoms or a cyano radical, is replaced by hydrogen by hydrolysis with an acid or base, by reaction with zinc, by reaction with a complex metal hydride, or by hydrogenolysis, (b) for those compounds where A is an ethylene radical, reduce a compound with the formula: with hydrogen in the presence of a catalyst, (c) for those compounds where A is a vinylene radical, a compound of the formula is dehydrated by means of toluene-p-sulfonic acid or methyltriphenoxyphosphonium iodide, (d) for those compounds where A is an ethylene radical, reacts a compound of formula IV with hydrogen in the presence of a catalyst, (e) a compound of the formula where Z represents a replaceable halogen atom or sulfonyloxy radical, is cyclized in the presence of a base, (f) a compound of the formula is reduced, (g) for the compounds where A is an ethylene radical, a compound with the formula is desulphurised in the presence of a catalyst such as Raney nickel, (h) for those compounds where A is a trans-vinylene radical, a compound of the formula is isomerized: with a thiophenol in the presence of a catalyst or with an acid, (i) for those compounds where A is a vinylene radical, the elements hydrogen and halogen are removed from a compound with the formula where Y is a halogen atom, upon heating with a base, wherein a compound which is an optically active enantiomer is prepared by cleavage of the racemic compound of formula I in the usual way, or by using one of the methods (a) to (i) where the intermediate product of the formulas II, III, IV, v, VI, VII, VIII or IX itself is a split isomer, and/or the compound obtained is optionally converted into the pharmaceutically acceptable acid addition salts thereof.