IL35641A - Piperazine and morpholine derivatives - Google Patents

Description

PIPERAZINE AND MORPHOLINE DERIVATIVES 35641 / 2 This invention relates to new morpholine and piperazine derivatives which possess valuable therapeutic properties, for example they possess thymoleptic activity in warm-blooded animals as demonstrated by the reversal of reserpine-induced hypothermia in mice, a standard test for thymoleptic activity, and these compounds are therefore useful in the treatment or prophylaxis of depressive illness in man. Furthermore, the compounds also possess depressant action on the central nervous system of warm-blooded animals as demonstrated by the reduction of spontaneous motility of mice, a standard test for central nervous depressant activity, and they are therefore useful in the treatment of anxiety and neurotic states in m n.

According to the invention there are provided new morpholine and piperazine derivatives of the formula: wherein the ring A together with the benzene ring to which it is fused forms the indole, N-alkylindole, -aralkylindole, benzoFb] furan, or benzol t3 tiophen ring, which ring is unsubstituted or is substituted by one methyl, ethyl, methoxycarbonyl or efrioxycarbonyl radical, and wherein X stands for the oxygen atom or for the imino (-NH-) radical, and the acid-addition salts thereof.

It is to be understood that the above definition of morpholine and piperazine derivatives encompasses all possible 35641 /3; stereoisomers thereof, and mixtures thereof, and in particular it includes individual optically-active enantiomorphs and racemic mixtures.

The ring A is preferably a fully-unsaturated 5-m ember ed ring containing one nitrogen, oxygen or sulphur . atom, such that together with the benzene ring to which it is fused it forms the indole, benzo jVj furan or benzo j j^ thiophen ring, which ring is radical ^tikyl^ubetituent-ef- tip-to- Carbon -atoma,- for example the methyl radical.

Particular compounds of the invention are for example morpholine derivatives of the formula: - wherein the ring A to which it is fused forms the indole,, N-alkylindble, benzo bj furan or benzo ^b thiophen ring, which ring is unsubstituted by one methyl or ethyl radical and the acid-addition salts thereof. that together with the benzene ring f.n wh i rh f. s fn n prl i t fovme tho indolOj boneso [b] furan or ongo [bjthioph n—g-iftgy whioh ring is unsubstituted or bears a single alkyl sub8tituen-t -of up to 5 oarbon atom83—for oxamplo the methyl radical".

Specific compounds of the invention are, for example, those specifically hereinafter described in Examples 1 to 11, and of these particularly active compounds are 2-(indol-4- yloxymethyl)morpholine, 2- (benzo [b ] furan-7-yloxymethyl )- morpholine ; 2- (benzo [b] thien-4-yloxymethyl )morpholine ; 2- (1, 4-benzodioxanr-5i-yloxymothyl )mor-pholino-; 2-(indol-5- yloxymethyl )morpholine ; 2- (indol-4-yloxymethyl )piperazine ; 2- (benzo [b ] thien.-5-yloxymethyl )morpholine ; 2- ( 3-methylbenzo- [b]thien-4-yloxymethyl)morpholine; 2- (3-methylbenzo [b] thien- 5-yloxymethyl )morpholine and 2- (l-benzyl-2-methylindol-5- yloxymethyl )morpholine and the acid-addition salts thereof.

Suitable acid-addition salts of the morpholine and piperazine derivatives of the invention are, for example, salts derived from an inorganic or organic acid, for example hydrochlorides, hydrobromides , phosphates, sulphates, oxalates, lactates, tartrates, acetates, salicylates, citrates, benzoates, β-naphthoates , adipates or 1,1-methylene-bis- (2-hydroxy-3- naphthoates ) , or acid-addition salts derived from acidic synthetic resins, for example sulphonated polystyrene resins, for example "Zeo-Karb" 225 ("Zeo-Kaj-b" is a Trade Mark).

According to a further feature of the invention there ' is provided a process for the manufacture of the morpholine and piperazine derivatives of the invention which comprises the removal of the removable a-arylalkyl or alkyl radical (s) from a compound of the formula :- wherein A has the meaning stated above, wherein X stands for the oxygen atom or for a radical of the formula -NR-and wherein R stands for a removable α-arylalkyl or alkyl radical .

A suitable removable α-arylalkyl radical is, for example, an alkyl radical of up to 4 carbon atoms substituted on the a-carbon atom by the phenyl radical, for example the benzyl radical. . A suitable removable alkyl radical is, for example, an alkyl radical of up to 4 carbon atoms, for example the methyl or isopropyl radical. The a-arylalkyl radical (s) may be removed by hydrogenolysis , for example by means of hydrogen in the presence of a catalyst, for example palladium, in a diluent or solvent, for example ethanol.

The hydrogenolysis may be carried out at a temperature of between 20 and 25°C., and it may be carried out at atmospheric pressure or at a pressure of up to 100 atmospheres.

Alternatively, the α-arylalkyl or alkyl radical (s) may be removed by the interaction of the starting material with an { alkyl or aryl chloroformate , for example methyl, ethyl, or phenyl chloroformate , in a diluent or solvent, for example benzene, at an elevated temperature, for example at the boiling point of said diluent or solvent, followed by hydrolysis of the alkoxy- or aryloxy- carbonyl derivative thereby obtained, for example with a base, for example an aqueous, alcoholic or aqueous alcoholic solution of an alkali metal hydroxide, for example potassium hydroxide.

It is to be understood that when the heterocyclic ring A is such that it may be affected by reducing conditions such as those used in hydrogenolysis, then if it is desired that the said ring be unchanged, non-reducing conditions such as those provided by use of a chloroformate and hydrolysis must be used. Alternatively, it is to be understood that the heterocyclic ring A may be altered during the process of the invention, for example a double bond may be reduced to a single bond.

The morpholine and piperazine starting materials for . the abovementioned process may be obtained by the interaction of a phenol of the formula :- wherein A has the meaning stated above, or a metal derivative thereof, for example an alkali metal derivative thereof, for o example the sodium derivative thereof, with a compound of the fornmla :- R wherein R and X1 have the meanings stated above, in a diluent or solvent, for example dimeth lformamide . Compounds of the last-mentioned formula wherein X ^ stands for the. oxygen atom are described and claimed in United Kingdom Appli-e-a-t-i-on-Νθ7-2<4€-6&-/-?0·. specification No.1, 310, 236.

Alternatively, the morpholine starting materials for the abovementioned process may be obtained by. the reaction of a phenol of the formula :- wherein A has the meaning stated above, with epichlorohydrin, followed by the interaction of the epoxide or chlorhydrin thus obtained with an amine of the formula RNHg, wherein R has the meaning stated above, followed by the interaction of the compound thus obtained of the formula :- wherein R and A have the meanings stated above, with a compound of the formula ZCJ^COZ1, wherein Z and Z1, which may be the same or different, stand for halogen atoms, for example chlorine or bromine atoms, followed by the cyclisation of the compound thus obtained of the formula :- wherein R and A have the meanings stated above to give the compound of the formula :- R wherein R and A have the meanings stated above, which compound is finally reduced with a complex metal hydride, for example lithium aluminium hydride.

According to a further feature of the invention there is provided a process for the manufacture of the morpholine derivatives of the invention which comprises the cyclisation of a compound of the formula :- wherein A has the meaning stated above and wherein Y stands for a displaceable radical, or of an acid-addition salt thereof.

A suitable value for Y is, for example, a halogen atom, for example the chlorine or bromine atom, or a sulphonyloxy radical, for example a radical of the formula -OS02OR"'" wherein R1 stands for hydrogen or for a lower alkyl or an aryl radical, for example the methyl, ethyl, phenyl or p-tolyl radical.

A suitable acid-addition salt of the starting material is, for example, a salt with a mineral acid, for example a hydrochloride, hydrobromide or sulphate.

The cyclisation process of the invention may be carried out in a diluent or solvent, for example water, or an alcohol, for example methanol, ethanol, isopropanol, n-butanol, t-butanol or ethylene glycol, or an ether, for example diethyl ether, tetrahydrofuran or dioxan, or an aromatic hydrocarbon, for example benzene or toluene, or a mixture of any of the abovementioned solvents, for example aqueous ethanol, aqueous methanol, aqueous dioxan or the two-phase water-toluene system; it may be carried out at ambient temperature or at an elevated temperature, for example at a temperature up to the boiling point of the diluent or solvent, for example at a temperature of between 0 and 100° C, for example at between 40 and 60° C; and it may be carried out in the presence of a base, for example an alkali or alkaline earth metal hydroxide, for example sodium, potassium or barium hydroxide.

The starting material for the last-mentioned process of the invention may be prepared in situ by the interaction of an epoxide of the formula :- wherein A has the meaning stated above, with a compound of the formula Η,,Ν.ΟΙ^ΟΕ^Υ, wherein Y has the meaning stated above. The conditions for this process are similar to those of the last-mentioned process of the invention, and the intermediate alkanolamine derivative is not isolated but is cyclised as it is formed.

Thus, according to a further feature of the invention there is provided a process for the manufacture of the morpholine derivatives of the invention which comprises the interaction of an epoxide of the formula :- wherein A has the meaning stated above, with a compound of the formula wherein Y has the meaning stated above, or with an acid-addition salt thereof.

The last-mentioned process of the invention may be carried out in a diluent or solvent, for example water, or an alcohol, for example methanol, ethanol, isopropanol, n-butanol, t-butanol or ethylene glycol, or an ether, for example diethyl ether, tetrahydrofuran or dioxare, or an aromatic hydrocarbon, for example benzene or toluene, or a mixture of any of the abovementioned solvents, for example aqueous ethanol, aqueous methanol, aqueous dioxare or the two-phase water-toluene system; it may be carried out at ambient temperature or at an elevated temperature, for example at a temperature up to the boiling point of the diluent or solvent, for example at a temperature of between 0 and 100° C. for example at between O and 60° C; and it may be carried out in the presence of a base, for example an alkali or alkaline earth metal hydroxide, for example sodium, potassium or barium hydroxide.

A suitable acid-addition salt of the compound of the formula is, for example, a salt with a mineral acid, for example a hydrochloride, hydrobromide or sulphate.

A particularly valuable compound of the formula HgN.Cl^Ci^Y is 2-aminoethyl hydrogen sulphate.

Preferred conditions for carrying out the last-mentioned process of the invention are as follows :- In stage 1, a mixture of one equivalent of an epoxide of the formula :- wherein A has the meaning stated above, more than one equivalent, for example between three and twenty equivalents, for example ten equivalents, of a compound of the formula :- H2N.CH2CH2Y wherein Y has the meaning stated above, for example 2-amino-ethyl hydrogen sulphate,' and approximately the same number of equivalents of a base, for example sodium hydroxide, as equivalents of the compound of the formula :- H2N.CH2CH2Y together with an aqueous diluent or solvent, for example aqueous ethanol, aqueous methanol or aqueous dioxan¾ is kept at a temperature of between 0 and 100°C, for example between 40 and 50° C, for at least 30 minutes, for example for one hour. In stage 2, a considerable excess of base, for example at least ten equivalents, for example eighteen equivalents of, for example, sodium hydroxide are then added and the mixture is kept at a temperature of between 0 and 100°C. for example between 40 and 55° C, for a further time of up to 30 days, depending upon the temperature. For example, at a temperature of between 40 and 55°C., the mixture is kept for, respectively, between 72 and 12 hours. The basic product is separated from non-basic material and then isolated and purified by conventional means.

The morpholine and piperazine derivatives of the invention may be converted into acid-addition salts thereof by the reaction of the morpholine or piperazine derivative in free base form with an acid by conventional means.

According to a further feature of the invention there are provided pharmaceutical compositions which comprise as active ingredient at least one of the morpholine or piperazine derivatives of the invention, or an acid-addition salt thereof in association with a pharmaceutically-acceptable diluent or carrier therefor.

The pharmaceutical compositions may be, for example, in a form suitable for oral or parenteral administration, for which purposes they may be formulated by means known to the art into the form of, for example, tablets, capsules, aqueous or oily solutions or suspensions, emulsions, injectable aqueous or oily solutions or suspensions, or dispersible powders.

The pharmaceutical compositions of the invention may also contain, in addition to the morpholine or piperazine derivative or salt thereof, one or more known drugs selected from neuroleptic agents, for example chlorpromazine, prochlorperazine, trifluoperazine and haloperidol; other sedative drugs and tranquillizers', for example chlordiazepoxide, phenobarbitone and amylobarbitone ; anticonvulsant drugs, for example primidone and phenytoin; β-adrenergic blocking agents, for example propranolol; drugs used in the treatment of 35641/2 Parkinson ''S disease, for example benzhexol; and other antidepressant drugs, for example i'mipramine, desipramine, amitriptyline, nortriptyline, drugs of the amphetamine type and monoamineoxidase inhibitors, for example phenelzine and mebanazine.

Preferred pharmaceutical compositions of the ■ invention are those suitable ■ for oral administra ion in unit dosage form, for example tablets and capsules, which contain between 1 and 100 mg. of active ingredient.

The^ pharmaceutical compositions of the invention will normally be administered to man, both for the treatment of anxiety and neurotic states and for the . treatment or prophylaxis of depressive illness, at such a dose that each patient receives a total of between 5 and 400 mg. of active ingredient per day, and preferably, if a highly active compound is used, a total of between 5 and 40 mg. per day, the composition being administered 3 or 4 times per day.

The invention is illustrated but not limited by the following Examples :- · .

Example 1 A mixture of 1- (benzo[b ]furan-7-yloxy )-2 ,3-epoxy-propane (5.30 g. ), 2-aminoethyl hydrogen sulphate (17.4 g. ) sodium hydroxide (11.2 g. ), ethanol (90 ml.) and water (55 ml.) is stirred and heated under reflux for 17 hours, and then evaporated to dryness under reduced pressure. The residue is partitioned between ethyl acetate (150 ml.) and water (100 ml.) and the aqueous layer is extracted with ethyl acetate (100 ml.). The combined ethyl acetate layers are dried oyer magnesium sulphate and evaporated to dryness.

The residual, free base is converted into the hydrogen oxalate thereof by conventional means, and the hydrogen oxalate is crystallised from methanol. There' is thus obtained 2-(benzo- [b]furan-7-yloxymethyl)morpholine hydrogen oxalate, m.p. 195-196°C.

The l-(benzo [b] uran-7-yloxy )-2,3-epoxypropane used as starting material may be obtained as follows :- A solution of potassium hydroxide (1.73 g. ) in ethanol (30 ml.) is added dropwise during 5 minutes to a stirred solution of 1- (benzo [b] furan-7-yloxy )-3-chloro-2-propanol (8 7 g.j prepared as described in United Kingdom Specification No.' 1,129,072) in ethanol (40 ml.) and the mixture is stirred for a further 2 hours. Aqueous 2N-hydrochloric acid is added until the pH of the mixture is 7, and the ethanol is removed by evaporation under reduced pressure. The residue is partitioned between water (100 ml.) and ethyl acetate (100 ml.) and the aqueous layer is extracted with ethyl acetate (50 ml.). The combined ethyl acetate layers are dried over magnesium sulphate and evaporated to dryness. There is thus obtained l-(benzo[b]furan-7-yloxy)-2,3-epoxypropane as an oil.

Example -3- 2.

A mixture of 4-benzyl-2- (indol-4-yloxymethyl )-morpholine (3.0 g.), 5% palladium-on-charcoal (1.0 g. ) and . ethanol (70 ml.) is shaken in an atmosphere of hydrogen at room temperature and atmospheric pressure for 12 hours, and is then filtered. The filtrate is evaporated to dryness, the residue is dissolved in the minimum quantity of a 5% v/v solution of methanol in ether and the solution is added to a l6 cm. x 13 mm. chromatography column of 10 g. of silica gel ("Plorisil"; "Plorisil" is a Registered Trade Mark) made up in ether. The column is eluted successively with 5 x 25 ml. of a 5% v/v solution of methanol in ether and 2 x 50 ml. of a 10% v/v solution of methanol in ether. The first 25 ml. fraction of eluate is discarded and the remaining eluate fractions are combined and evaporated to dryness.

The residue is triturated with a mixture of ethyl acetate, ether and cyclohexane and there is thus obtained as solid product 2- (indol'-4-yloxymethyl)morpholine, m.p. 136.5-139 · 5°C .

The 4-benzyl-2- (iridol-4-yloxymethyl )morpholine used as starting material may be obtained as follows :- A mixture of 2 , 3-epoxy-l- (indol-4-yloxy )propane ( .4 g., prepared as described in United Kingdom Specification No. 1,138,969) and benzylamine (3.08 g. ) is heated at 95-100°C. for 19 hours and is then cooled and stirred with petroleum ether (b.p. 60-80°C). The petroleum ether solution is ■ 4 discarded, the insoluble gum is dissolved in ethyl acetate (150 ml.) and the solution is extracted twice with aqueous N-tartaric acid solution (200 ml. and 100 ml.). The combined extracts are washed with ethyl acetate (50 ml.) and then basified to pH 9 with aqueous 5N-sodium hydroxide solution. The mixture is extracted twice with ethyl acetate (200 ml. and 100 ml.) and the combined extracts are washed with water (50 ml.), dried over magnesium sulphate and evaporated to dryness. To a stirred, ice-cooled solution of the 3-benzylamino-l- (indol-^-yloxy )-2-propanol thus obtained (3.82 g. ) in dry, acid-free methylene chloride (75 ml.) are added, simultaneously and dropwise during 20 minutes, a solution of chloroacetyl chloride (1.06 ml.) in methylene chloride (10 ml.) and a solution of triethylamine (1.80 ml.) in methylene chloride (10 ml.). The mixture is stirred at room temperature. for 1.5 hours and is then washed successively with aqueous N-tartaric acid solution (20 ml., twice), water (20 ml.), 0% aqueous potassium hydrogen carbonate solution (20 ml.) and water (20' ml.). The methylene chloride solution is then dried and evaporated to dryness and the 3~(N-benzyl-chloroacetamido)-l- (indol-4-yloxy )-2-propanol thus obtained (^.5^ g. ) is dissolved in methanol. (30 ml.). The solution is added to a solution of sodium (0.281 g. ) in methanol (30 ml.) and the mixture is heated under reflux for 6 hours, kept at room temperature for 17 hours and then evaporated to dryness under reduced pressure. The residue is partitioned between water (50 ml.) and chloroform (100 ml.). The chloroform layer is separated, washed with water (20 ml.), dried and evaporated to dryness. A solution of the 4-benzyl- 2- (indol-4-yloxymethyl)morpholin-5-one thus obtained (3.76 g. ) in tetrahydrofuran (85 ml. ) is added under an atmosphere of nitrogen to a stirred suspension of lithium aluminium hydride (0.86 g. ) in tetrahydrofuran (25 ml.) and the mixture is stirred and heated under reflux for 4 hours and is then kept at room temperature for 17 hours. The mixture is evaporated to dryness under reduced pressure and the residue is partitioned between ether (150 ml.) and 20% aqueous potassium sodium tartrate solution (50 ml.). The aqueous layer is extracted with ether (100 ml. ) and the combined ethereal solutions are dried and evaporated to dryness. There is thus obtained 4-benzyl-2- (indol-4-yloxymethyl )morpholine as an oil.

Example-4- 3 A mixture of 2- (benzo [b] thien-4-yloxymethyl)-4-isopropyl morpholine (5.3 g.), phenyl chloroformate (4 g.) and benzene (50 ml.) is heated under reflux for 4 hours and then evaporated to dryness under reduced pressure. A solution of potassium hydroxide (10 g. ) in ethanol (50 ml.) is added and the mixture is heated under reflux for 48 hours and then evaporated to dryness under reduced pressure. The residue is partitioned between ethyl acetate and water and the ethyl acetate layer is separated, washed with water, dried over magnesium sulphate and evaporated to dryness under reduced pressure. The residual free base is converted into the hydrogen oxalate thereof by conventional means and the hydrogen oxalate is crystallised from methanol. There is thus obtained 2- (benzo [b] thien-4-yloxymethyl)morpholine hydrogen oxalate, m.p. l68°C.

The 2- (benzo [b] thien-4-yloxymethyl)-4-isopropyl-morpholine used as starting material may be obtained as follows :- Chloroacetyl chloride (2.8 g. ) is added dropwise to a stirred, ice-cooled mixture of 1- (benzo [b] thien-4-yloxy )-3~ isopropylamino-2-propanol (6 g. ; prepared as described in United Kingdom Specification No. 1,089,769), triethylamine (10 g. ) and methylene chloride (50 ml.) and the mixture is stirred for 12 hours, washed with aqueous 2N-hydrochloric acid, dried and evaporated to dryness. The residue, which consists essentially of 1- (benzo [b] thien-4-yloxy )-3- (N-isopropylchloro-acetamido)-2-propanol, is added to a solution of sodium (0.6 g.) in methanol (50 ml.) and the mixture is heated under reflux for 12 hours and then evaporated to dryness under reduced pressure. The residue is partitioned between chloroform and water and the chloroform layer is separated, dried over magnesium sulphate and evaporated to dryness under reduced pressure. The residue, which consists essentially of 2- (benzo [b] thien-^-yloxymethyl^^-isopropylmorpholine-S-one, is dissolved in ether (30 ml.) and the solution is added dropwise to a stirred suspension of lithium aluminium hydride (1.0 g. ) in ether (100 ml.). The mixture is stirred and heated under reflux for 3 hours and water (1 ml.), 10% aqueous sodium hydroxide solution (1 ml.) and water (3 ml.) are successively added. The ethereal solution is separated, dried over magnesium sulphate and evaporated to dryness.

There is thus obtained as oily residue 2- (benzo [b] thien-4-yloxymethyl )-4-isopropylmorpholine.

Example -5- A mixture of 2-aminoethyl hydrogen sulphate (10.9 g. ) and a solution of sodium hydroxide (4 g. ) in water (3 ml.) is stirred for 5 minutes, a solution of 1- (benzo [b] thien-4-yloxy )-2,3-epoxypropane (4 g.; prepared as described in United Kingdom Specification No. 1,089,769) in methanol (30 ml.) is then added and the mixture is stirred at room temperature for 2 hours. A solution of sodium hydroxide (8 g. ) in water (6 ml.) is added and the mixture is stirred and heated at 60°C. for 24 hours. The reaction mixture is partitioned between water (150 ml.) and ethyl acetate (150 ml.) and the aqueous layer is extracted with ethyl acetate (100 ml.). The combined ethyl acetate layers are dried over magnesium sulphate and evaporated to dryness. The residual oil is dissolved in the minimum quantity of ethyl acetate and the solution is added to a 19 cm. x 2 cm. chromatography column of 24 g. of silica, gel ("Plorisil"; "Plorisil" is a Registered Trade Mark) made up in ethyl acetate. The column is eluted with ethyl acetate. The initial 6 x 10 ml. fractions of eluate are discarded and the remaining eluate fractions are combined and evaporated to dryness. The residual free base is converted into the hydrogen oxalate thereof by conventional means and the hydrogen oxalate is crystallised from methanol. There is thus obtained 2- (benzo [b] thein-4-yloxymethyl )morpholine hydrogen oxalate, m.p. l65-l68°C.

The process described above is repeated except that an equivalent amount of the appropriate 1-heterocyclyloxy- 2, 3-epoxypropane (prepared from the appropriate hydroxyindole or hydroxybenzo [b] thiophen) is used in place of the l-(benzo- [b] thien-4-yloxy )-2, 3-epoxypropane, and there are thus obtained the following compounds :-2-(indol-4-yloxymethyl)morpholine, m.p. 137~l110oC.j 2- (indol-5-yloxymethyl )morpholine hydrogen oxalate, m.p. 197-200°C; 2- (benzo [b] thien-5-yloxymethyl )morpholine hydrogen oxalate, m.p. 166-169° C . (with decomposition); 2- (3-methylbenzo [b]thien-5-yloxymethyl)morpholine hydrogen oxalate, m.p. 166°C. (with decomposition); 2- (3-methylbenzo [b] thien-6-yloxymethyl)morpholine hydrogen oxalate, m.p. 196-199"°C Example--6- 5 A solution of l,il-dibenzyl-2-(indol-4-yloxymethyl)-piperazine dihydrochloride (2.2 g. ) in a mixture of ethanol (100 ml.) and water (25 ml.) is shaken with a 5% palladium-on-charcoal catalyst (0.5 g. ) in an atmosphere of hydrogen at a temperature of between 20 and 25° C. and at atmospheric pressure until the uptake of hydrogen ceases. The mixture is filtered, the filtrate is evaporated to dryness and the residue is crystallised from methanol. There is thus obtained 2- (indol-4-yloxymethyl )piperazine dihydrochloride , m.p. 295°C (with decomposition) .

The 1, 4-dibenzyl-2- (indol-4-yloxymethyl)piperazine dihydrochloride used as starting material may be obtained as follows :- Sodium hydride (0.75 g. of a 50% dispersion in oil) is added to a stirred solution of 4-hydroxyindole (2.0 g. ) in dry dimethylformamide (30 ml.), the temperature of the mixture being maintained between 20 and 25°C A solution of l,4-dibenzyl-2-chloromethylpiperazine (4.7 g. ) in dimethyl-formamide (30 ml.) is added and the mixture is heated at 100°C. for 4 hours and then cooled. Water (120 ml.) and ethyl acetate (150 ml. ) are added, the mixture is shaken and the layers are separated. The ethyl acetate layer is washed with water (100 ml.), dried over magnesium sulphate and evaporated to dryness. The residual oil is dissolved in the minimum quantity of acetone and the solution is added to a 38 cm. x 2 cm. chromatography column of 48 g. of silica gel ("Florisil" ; "Florisil" is a Registered Trade Mark) made up in petroleum ether (b.p. 60-80°C). The column is eluted with' a 10$ v/v solution of acetone in petroleum ether (b.p. 60-80°C.) until the eluant contains no further solute. The combined eluates are evaporated to dryness and the residual free base is converted into the hydrochloride thereof by conventional means. The hydrochloride is crystallised from ethanol and there is thus obtained l,4-dibenzyl-2-(indol-4-yloxy-methyl)piperazine dihydrochloride, m.p. 245-247°C.

Example -7-- 6 A mixture of l,4-dibenzyl-2- (benzo [b] thien-4-yloxy-methyl )piperazine (8.1 g. isolated by conventional means from the dihydrochloride thereof), benzene (200 ml.) and phenyl chloroformate (8.5 ml.) is heated under reflux for 4 hours. The benzene is removed by evaporation and to the residue is added a solution of potassium hydroxide (35 g.) in ethanol (150 ml.). The mixture is stirred and heated under reflux for 64 hours and then filtered. The filtrate is evaporated to dryness and the residual solid is partitioned between ethyl acetate (150 ml.) and water (150 ml.). The ethyl acetate layer is separated and extracted with dilute aqueous hydrochloric acid (150 ml.) and the acidic extract is made alkaline and extracted with ethyl acetate (150 ml.). The ethyl acetate extract is dried and evaporated to dryness.

The residual free base is converted into the hydrochloride thereof by conventional means and the hydrochloride is crystallised from ethanol. There is thus obtained 2-(benzo-[b]thien-4-yloxymethyl)piperazine dihydrochloride, m.p. 272-276°C.

The process described above is repeated except that 1, -dibenzyl-2- (3-methylbenzo [b] thien-5-yloxymethy1 )piperazine or 1, -dibenzyl-2- (3-methylbenzo [b] thien-6-yloxymethyl)-piperazine is used as starting material in place of 1,4- dibenzyl-2- (benzo [b] thien-4-yloxymethyl )piperazine . There is obtained, respectively, 2- (3-methylbenzo [b]thien-5-yloxy- hydrochloride methyl)piperazine,/m.p. 2l6-219°C. or 2- (3-methylbenzo [b]-thien-6-yloxymethyl )piperazine dihydrochloride , m.p. 292°C. (with decomposition).

The 1, -dibenzyl-2- (benzo [b] hienyloxymethyl )piperazine derivatives used as starting materials may be obtained by a similar process to that described in the second part of Example 6, except that the appropriate hydroxybenzo [b] thiophen is used in place of 4-hydroxyindole . Thus from 4-hydroxy-benzo [b] thiophene there is obtained 1, -dibenzyl-2- (benzo [b] -thien-4-yloxymethyl)piperazine dihydrochloride, m.p. 224-226°C. from 5-hydroxy-3-methylbenzo [b] thiophene there is obtained 1, 4-dibenzy1-2- (3-methylbenzo [b] thien-5-yloxymethyl)piperazine dihydrochloride, which is used without further purification-and from 6-hydroxy-3-methylbenzo [b] thiophene there is obtained 1, 4-dibenzyl-2- (3-niethylbenzo [b] thien-6-yloxymethyl )piperazine dihydrochloride, which is used without further purification. Example ~8"~ ? A solution of 1.0 g. of 4-benzyl-2- (l-benzyl-2-methyl-indol-5-yloxymethyl )morpholine hydrogen oxalate in 30 ml. of absolute ethanol is shaken in an atmosphere of hydrogen at ambient temperature and at a pressure of one atmosphere until uptake of hydrogen ceases. The mixture is filtered, the filtrate is evaporated to dryness under reduced pressure and the residue is triturated with ethyl acetate. There is thus obtained as solid product 2-(l-benzyl-2-methylindol-5-yloxy-methyl)morpholine hydrogen oxalate, m.p. 155-157°C.

The -benzyl-2- (l-benzyl-2-methylindol-5-yloxymethyl )-morpholine hydrogen oxalate used as starting material may be obtained as follows :- A solution of 3 g. of ethyl l-benzyl-5-hydroxy-2-methylindole-3-carboxylate in a mixture of 60 ml. of aqueous 2N-sodium hydroxide solution and 10 ml. of ethanol is stirred and heated under reflux in an atmosphere of nitrogen for 3 hours. The mixture is cooled, diluted with 100 ml. of water and extracted twice with 50 ml. of ether each time, and the extracts are discarded. The aqueous layer is acidified with aqueous 2N-hydrochloric acid and extracted with ethyl acetate (3 x 100 ml.), and the combined ethyl acetate extracts are dried and evaporated to dryness under reduced pressure. The residue is crystallised from ethyl acetate and there is thus obtained l-benzyl-5-hydroxy-2-methylindole-3-carboxylic acid, m.p. 177-179°C 3 G. of this product is heated over free flame at l80-200°C. for about 5 minutes. The residue is cooled and dissolved in benzene and the solution is added to a chromatography column of 50 g. of silica gel ("Florisil"; "Florisil" is a Registered Trade Mark) made up in benzene. The column is eluted with benzene and the combined eluate is evaporated to dryness. The residue is crystallised from a mixture of benzene and petroleum ether (b.p. 60-80°C.) and there is thus obtained l-benzyl-5-hydroxy-2-methylindole , m.p. 108-110°C. 0.6 G. of a 60% dispersion of sodium hydride in mineral oil is added to a stirred solution of 3.6 g. of the above compound in 50 ml. of dry dimethyl sulphoxide which is heated at 50-60° C. in an atmosphere of nitrogen, and the mixture is stirred and heated until evolution of hydrogen ceases and a clear solution is obtained. A solution of 2.25 g. of 4-benzyl- (described in United Kingdom Specification No. ^ rf rffQ- in 75 ml. of dry dimethyl sulphoxide, followed by 1.7 g. of potassium iodide, are added and the mixture is stirred and heated at 120°C. in an atmosphere of nitrogen for 18 hours. The mixture is cooled, diluted with 300 ml. of water and extracted with ethyl acetate ( 3 x 100 ml.). The combined extracts are washed twice with 50 ml. of aqueous 2N-sodium hydroxide solution each time and four times with water, dried and evaporated to dryness under reduced pressure. The residue is crystallised from cyclo-hexane and there is thus obtained 4-benzyl-2- (l-benzyl-2-methylindol-5-yloxymethyl)morpholine, m.p. 105-107°C. The corresponding hydrogen oxalate is prepared by conventional means and is crystallised from methanol. It has m.p. 195-197°C .

Example -9- 8 A mixture of 4-hydroxybenzo [b] furan (1.34 .)s epi-chlorohydrin (1.5 ml.) and a solution of potassium hydroxide (0.65 g.) in water (10 ml.) is stirred at room temperature for 24 hours and then extracted with ethyl acetate. The extract is dried and evaporated to dryness and a solution of the residual crude epoxide in methanol (30 ml. ) is added to a stirred suspension of 2-aminoethyl hydrogen sulphate (6 g. ) in aqueous l8N-sodium hydroxide solution (5 ml.). The mixture is stirred at room temperature for 2 hours, further aqueous l8N-sodium hydroxide solution (6 ml.) is added and the mixture is stirred at 60°C. for 6 hours and then poured into a mixture of ice and water. The mixture is extracted with ethyl acetate and the extract is dried and -evaporated to dryness. The residue is purified by preparative thin-layer chromatography on silica gel plates using the solvent system ethyl acetate: ethanol: triethylamine (100: 40: 3 parts v/v) and the pure free base is converted into the hydrochloride thereof. There is thus obtained 2- (benzo [b]-furan-4-yloxymethyl )morpholine hydrochloride, m.p. ΐ44-ΐ46°0. (crystallised from ethanol).

Example 19- 9 A solution of 4-benzyl-2- (3-ethoxycarbonyl-2-methyl-benzo [b]furan-5-yloxymethyl)morpholine hydrochloride (0.55 g.) in ethanol (50 ml.) is shaken with a 5% palladium-on-charcoal catalyst in an atmosphere of hydrogen at room temperature and atmospheric pressure until uptake of hydrogen ceases.

The mixture is filtered and the filtrate is evaporated to dryness under reduced pressure. The residue is dissolved in aqueous N-sodium hydroxide solution and the solution is extracted with ethyl acetate. The extract is dried and evaporated to dryness and the residual free base is purified by preparative thin layer chromatography on silica gel plates using the solvent system ethyl acetate: ethanol: triethylamine 100:40:3 v/v to develop the plate. The free base is converted into the hydrogen oxalate thereof by conventional means, and there is thus obtained 2-(3-ethoxy-carbonyl-2-methylbenzo [b] furan-5-yloxymethyl )morpholine hydrogen oxalate, m.p. l40-l45°C The 4-benzyl-2- (3-ethoxycarbonyl-2-methylbenzo [b] -furan-5-yloxymethyl )morpholine hydrochloride used as starting material may be obtained as follows :- Sodium hydride (0.5 g. of a 50% dispersion in oil) is added slowly to a stirred suspension of ethyl 5-hydroxy-2-methylbenzo [b] furan-3-carboxylate (2.04 g. ) in dry dimethyl sulphoxide (10 ml.). Potassium- odide (1.1 g. ) and 4-benzyl-2-chloromethylmorpholine (1.5 g.) are added and the mixture is heated at 130°C. for 2.5 hours and then cooled and poured into a cold mixture of aqueous N-hydrochloric acid (100 ml.) and ether (100 ml.). The solvent is decanted from the gummy insoluble hydrochloride and discarded, and the gum is dissolved in aqueous N-sodium hydroxide solution. The solution is extracted with ether and the extract is dried and evaporated to dryness. The residue is dissolved in toluene and the solution is added to a chromatography column of silica gel ("Plorisil"; "Plorisil" is a Registered Trade Mark) and the column is eluted with a mixture of toluene and ethyl acetate (3 : 1 v/v). The eluate is evaporated to dryness and the residual oil is converted into the hydrochloride thereof by conventional means. There is thus obtained 4-benzyl-2- (3-ethoxycarbonyl-2-methylbenzo [b] furan-5-yloxymethyl ) morpholine hydrochloride as an oil which, is. used without further purification.

Example -ii- 10 A mixture of 4-hydroxy-3-methylbenzo [b] thiophen (3.2 g.), epichlorohydrin (3 ml.) and a solution of potassium hydroxide (1.3 g.) in water (16 ml.) is stirred at room temperature for 21 hours and then extracted with ethyl acetate. The extract is dried and evaporated to dryness. A solution of the residual epoxide in methanol (50 ml.) is added in an atmosphere of nitrogen to a stirred suspension of 2-aminoethyl hydrogen sulphate (10.8 g in aqueous l8N-sodium hydroxide solution (10.8 ml.) and the mixture is stirred at room temperature for 2 hours.

Further aqueous l8N-sodium hydroxide solution (11.4 ml.) o is added and the mixture is stirred for 24 hours at 60 C. under an atmosphere of nitrogen and then poured into a mixture of ice and water. The mixture is extracted with ether and the extract is dried. Excess of a 1% ethereal solution of oxalic acid is added and the mixture is filtered The free base is isolated from the oxalate salt by conventional means and is purified by preparative thin layer chromatography on 1 mm. plates of silica gel using the solvent system ethyl acetate : ethanol : triethylamine 100 : 40 : 3 v/v to develop the plate.

The purified base is reconverted to the hydrogen oxalate thereof by conventional means and this salt is crystallised from a mixture of methanol and ether. There is thus obtained 2- (3-methylbenzo [bJthien-ll-yloxymethyDmorpholine hydrogen oxalate, m.p. 125-127°C.

The 4-hydroxy-3-methylbenzo [bjthiopheneused as starting material may be obtained as follows :- A solution of 4-hydroxy-3-methylbenzo [b] thiophene-2-carboxylic acid (12 g. ) in pyridine hydrochloride (25 g.) is heated under reflux in an atmosphere of nitrogen for 6 hours. The mixture is- poured into water and the aqueous mixture is extracted with ethyl acetate. The extract is dried and evaporated to dryness and the residual oil is extracted with boiling petroleum ether (b.p.80 - 100°C). The ethereal solution is evaporated to dryness under reduced pressure and the residue is crystallised from petroleum ether (b.p.60 - 80°C). There is thus obtained 4-hydroxy-3-niethylbenzo [b] thiophene, m.p. 98 - 99°C.

Claims (10)

1. 35641/ 3 ■What we claim is : - 1. 'Morpholine and piperazine derivatives of the formula wherein the ring A together with the benzene ring to which it is fused forms the indole,' N-alkylindole , N-aralkylindole , benzo[ ]furan, or benzo [b ]thiophen ring, which ring is unsubstituted or is substituted by one methyl, ethyl, methoxy-carbonyl or ethoxycarbonyl radical, and wherein X stands for the oxygen atom or for the imino C- H- ). radical, and the acid-addition salts thereof.

2. , Morpholine and piperazine derivatives as claimed in claim 1 wherein the ring A together with' the benzene ring to which it is fused forms the indole, benzo [b ]furan or benzo[b Jthiophen ring, which ring is unsubstituted or bears a methyl radical and the acid-addition salts thereof.

3. Morpholine derivatives of the formula :- wherein the ring A together with the benzene ring to which it is fused forms the indole,' N-alkylindole, benzo [-'b Jfuran, or 3S641/3 benzo[b jthiophen ring, which ring is unsubstituted.ior is substituted by one methyl or .ethyl radical' and the a,cid- addition salts thereof'.;: ■ ■'" , ■ · y, '· , · . Morpholine derivatives as claimed- in claim 3 wherein -the ,ring A has the . meaning stated in claim 2, and V the acid-addition salts thereof. J - 5. The compound 2- (indol-4-yioxymethyl )morpholine and the acid-addition salts thereof. j 6. The compound 2- (benzo [b ]furan-J-yloxymethyl )- ! morpholine and the acid-addition salts thereof. 7. The compound 2- (benzo [ Jthien-^-yloxymethyl )- morpholine and the acid-addition salts thereof. 8. The compound 2- (indol-5-yloxymethyl )morpholine and the acid-addition salts thereof. 9. The compound 2- (indol-^-yloxymethyl )piperazine and the acid-addition salts thereof. 10. The compound 2- Cbenzo [b jthien-5-yloxymethyl }- morpholine and the acid-addition salts thereof. ■11. The compound 2- (3-methylbenzo [b )- morpholine and the acid-addition salts thereof. .12. The compound 2- (3-methylbenzo [b ]thien-5-yloxymethyl ).- morpholine and the acid-addition salts thereof. ■13. The compound 2- (l-benzyl-2-methylindol-5-yloxymethyl )- morpholine and the acid-addition salts thereof. 1 . Acid-addition salts of the morpholine and piperazine derivatives, claimed in any of claims 1 to 13, which are hydrochlorides, hydrobrom'ides'j' phosphates-, sulphates, ·.... ■■ oxalates, ' lactates, tartrates , acetates , salicylates,' ·. · · citrates, benzoates, β-naphthoates , adipates, or 1 , 1-methylene-bis- (2-hydroxy-r.3-naphthoates ),, · or acid-addition salts-derived from sulphonated polystyrene1' resins . . 15·' Acid-addition salt S' of the morpholine- derivatives claimed in any of claims 3 to 7, which are hydrochlorides, hydrobromides , phosphates, sulphates, oxalates, lactates, tartrates, acetates, salicylates, citrates, benzoates, β-naphthoates, adipates or 1 , 1-methylene-bis- (2-hydroxy-3-naphthoates ) , or acid-addition salts derived from sulphonated polystyrene resins. 16. A process for the manufacture of the morpholine and piperazine derivatives and the acid-addition salts thereof, "claimed in any of claims 1 to 15, which comprises the removal of the removable a-aryl-alkyl or alkyl radical (s ) f om a compound of- the formula : - wherein A has the meaning stated in any of claims 1 to 1 wherein stands for the oxygen atom or for a radical of the formula -NR-, and wherein R stands for a removable a-aryl-alkyl or alkyl radical, whereafter if desired the the morpholine or piperazirie derivative 'in free'' base form "' is reacted with an acid in order to form an' acid-addition salt thereof.. 17. A process as claimed in claim l6 wherein R stands for the benzyl radical. 18. A process as claimed in claim ΐβ or 17 wherein the ct-aryl-alkyl radical (s) is (are) removed by hydrogenolysis 19. A process as' claimed in claim 16 wherein R stands for the methyl or isopropyl radical. 20. A process as claimed in claims l6, 17 or 19 wherein the a-aryl-alkyl or alkyl radical (s ) is (are) removed by the interaction of the starting material with an alkyl or aryl chloroformate , followed by hydrolysis of the alkoxy- or aryloxy-carbonyl derivative thereby obtained. 21. A process as claimed in claim 20 wherein the chloroformate is methyl, ethyl or phenyl chloroformate . 22. A process for the manufacture of the morpholine derivatives and the acid-addition salts thereof, claimed in any of claims 3 to 8, 10 to 13, and 15, which comprises the cyclisation of a compound of the formula :- OCH2. CHOH. CH2NH. CH2C Y I A wherein A has the meaning stated in either of claims 2 or 3 and wherein Y stands, for a displaceable radical, or- of an acid-addition salt thereof, or which comprises the interaction of an epoxide of the formula :- wherein A has the meaning stated in either of claims 2 or 3 with a compound of the formula H2N. CH,-,CH2Y. wherein Y has the meaning stated above, or with an acid-addition salt thereof, whereafter if desired the morpholine derivative in free base form is reacted with an acid in order to form an acid-addition salt thereof. 23. A process as claimed in claim 22 wherein Y stands for a halogen atom or for a . sulphonylaxy radical. 2

4. A process as claimed in claim 23 wherein Y stands for the chlorine or bromine atom, or for a radical of the formula , wherein R1 stands for hydrogen or for the methyl, ethyl, phenyl or' p-tolyl radical. 2

5. A process as claimed in claim 22 wherein the starting material of the formula H^N.CH^G^Y is 2-aminoethyl hydrogen sulphate. 2

6. A process as claimed in any of claims 22 to 25 wherein the acid-addition salt of the starting material is a hydrochloride, hydrobromide or sulphate. 2

7. A process as claimed in any of claims 22 to 26 which is carried out in a diluent or solvent at a temperature of between 0 and 100°C, and which is carried out in the presence of a base. 2

8 . Ά. process as claimed in claim 27 wherein the base is sodium hydroxide. 2

9 . ' A process as. claimed' in any of claims 22 to 28 ,\ characterised in that in stage 1 a mixture of one equivalent of an epoxide of the formula : - wherein A has the meaning stated in either of claims 2 or '3, more than one equivalent of a compound of the formula H2 CH2CH2Y, wherein Y has the meaning stated in claim 22, 23 or 2^ and approximately the same number of equivalents of a base as equivalents of the compound of the formula H^NCH^CH^Y, together with an aqueous diluent or solvent, is kept at a temperature of between 0 and 100°C. for at least 30 minutes; and in stage 2 a considerable excess of the base is added and the mixture is kept at a temperature of between 0 and 100 °C. for up to 30 days whereafter the product is isolated and purified by conventional means. 30. A process as claimed in claim 29 wherein there are used between three and twenty equivalents of the compound of the formula H^NCH^CH^Y, wherein in stage 2 the considerable excess of the base is at least ten equivalents, and-„ which is carried out at a temperature of between ,40 and 55°C, in both 35481/2 · J, stage 1 and stage 2. . ■ v 31. . -Pharmaceutical compositions which comprise as active ingredient at least one Of the morpholine or piperazine derivatives, or .an acid-addition salt thereof, claimed in any of claims 1 to 15, in association with a pharmaceu ica ly-acceptable diluent or carrier therefor. 32. Pharmaceutical compositions as claimed in claim 31 which are in the form of tablets, capsules, aqueous or oily solutions or suspensions, emulsions, injectable aqueous or oily solutions or suspensions, or dispersible powders. 33. Pharmaceutical compositions as claimed in claim 31 or 32 which also contain, in addition to the morpholine or piperazine derivative or salt thereof, one or more known drugs selected from neuroleptic agents, other sedative drugs and tranquillizers, anticonvulsant drugs, {.-adrenergic blocking agents, drugs used in the treatment of Parkinson's disease and other antidepressant drugs, 3^. Pharmaceutical compositions as claimed in claim 31, 32 or 33 which are suitable for oral administration in unit dosage form and which contain between 1 and 100 mg. of active ingredient. 35. Morpholine derivatives and acid-addition salts thereof, claimed in any of claims 3 to 7 and 15, as hereinbefore specifically described in Examples 1 to 3. 36. Morpholine and piperazine derivative's and acid-addition salts thereof, claimed in any of claims 1 to 15, as hereinbefore specifically described in Examples 1 to

10. f 37. A process for the manufacture of morpholine and piperazine derivatives and acid-addition salts thereof, claimed in any of claims 16 to '30, as hereinbefore specifically described in Examples 1. to 10. AGENTS FOR APPLICANTS PH, 22335 IJSB HJE : 26.4.74