GB1576216A - 2-(7-indenyloxymethyl)-morpholine derivatives and process of producing them - Google Patents

Description

(54) 2-(7-INDENYLOXYMETHYL)-MORPHOLINE DERIVATIVES AND PROCESS OF PRODUCING THEM (71) We, YAMANOUCHI PHAR MACEUTICAL CO. LTD., a Company organised and existing under the laws of Japan, of No. 5-1, Nihonbashi-Honcho 2chome, Chuo-ku, Tokyo, Japan, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: This invention relates to an improvement in or modification of the invention of British Patent Application No. 1762/76 (1,535,276) (hereinafter referred to as the main invenrion).

According to the main invention, there is provided a compound represented by the formula

wherein R' and R3 each represents a hydrogen atom, a lower alkyl group, or a phenyl group; R2 represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, a phenyl group, or a benzyl group; and one of the dotted lines represents a single bond and the other represents a double bond; and the acid salts thereof.

The main invention also includes a process of producing these compounds, a process of preparing formulations containing these compounds, and is further concerned with the uses of these compounds.

The present invention is based on the discovery that one compound included in the scope of the main invention, but not disclosed practically in the specification thereof (so far as concerns its particular physical and chemical properties) is particularly useful as an antidepressant agent. It is also based on the discovery of a novel process of producing such compound, which process is not described in the specification of the main invention.

Anti-depressant agents having a morpholine ring are already known as disclosed in, for example,-British Patent No. 1,138,405 and British Patent No. 1,260,886.

The compound which is believed to have the best activity among the compounds disclosed in these patent specifications is 2-(2-ethoxy- phenoxymethyl)morpholine, which is usually known as Viloxazine (see "Nature", 238, 157-158 (1972)). A series of studies made by K. B. Mallion, A. H. Todd, R. W. Turner, et al (the inventors of Viloxazine) suggests a relationship between the chemical structures and pharmacological activities of the known compounds. That is, it is preferred that the compound has one substituent at the 2-position of a phenoxy group bonded to morpholine.

Furthermore, when the phenoxy group forms a fused ring, it is preferred that, for example, a tetralin-type ring is formed by the notional condensation with a tetramethylene group.

Against this, when the condensed ring forms an indane-type ring by the condensation with a trimethylene group, the pharmacological effect becomes less.

According to this invention there is provided an acid addition salt of 2-(7-indenyloxymethyl)morpholine represented by the general formula

In the spedfication of the main invention, the compound obtained in Example 10 is described as 2-(4- or 7-indenyloxymethyl) morpholine, having a maleate with a melting point of 135--137"C. As the result of further investigations, the present inventors have dfs- covered that the compound obtained in Example 10 is, in fact, a mixture of 2-(7indenyloxymethyl ) morpholine (hereinafter, referred to as the 7-isomer), and 2-(4-indenyl oxymethyl)morpholine (hereinafter, referred to as the 4-isomer) similar to the compound obtained in Example 16 of the specification of the main invention. Furthermore, the inventors have further succeeded in separating the product into 2-(7-indenyloxymethyl)moipholine maleate melting at 154-1560C and 2 - (4 - indenyloxymethyl)morpholine maleate melting at 167--1690C. This separation and the resultant compounds are not practically disclosed in the specification of the main invention. It has further been experimentally found that the 2- (7-indenyloxy- methyl)morpholine acid addition salts obtained have better pharmacological effects compared with the 4-isomer and hence should be favoured for use as medicamenti.

The inventors have further succeeded in discovering a novel process of producing the desired product different from the processes described in the specification of the main invention, and also an isomerisation process for producing the desired product.

That is, 1,2-epoxy-3-(7-indenyloxy)propane and/or 1,2 - epoxy - 3 - (4 - indenyloxy)propane represented by the formula II

wherein one of the dotted lines represents a single bond and the other represents a double bond, is reacted with an amine represented by the general formula III HNH2-CH,-Z III wherein Z represents a halogen atom or -OSO,R4 (wherein R4 represents a hydrogen atom, an aryl group, or a lower alkyl group) in the presence of a base to produce a mixture of 2 - (7 - indenyloxymethyl)morpholine and 2 - (4 - indenyloxymethyl)morpholine, shown by the general formula IV

wherein the dotted lines have the same meaning as above, and to the mixture obtained is added an acid in an amount less, and preferably only slightly less, than the stoichiometric amount required to isomerise 2z(4-indenyloxy- methyl)morpholine whereby the acid addition salt of 2 - (7 - indenyloxymethyl)morpholine shown by the general formula I

is obtained.

Now, the lower alkyl group shown by R4 in the compounds represented by general formula III is a straight or branched chain alkyl group having up to 6 carbon atoms. Practical examples of the alkyl group are a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, neopentyl, hexyl or isohexyl group. Examples of the halogen Z of the compound of general formula III are chlorine, bromine, or iodine.

The aryl group shown by R4 in the compound includes a phenyl and p-tolyl group.

The 2 - (indenyloxymethyl)morpholine (a mixture of 7-isomer and 4-isomer) shown by general formula IV is usually obtained by reacting 1,2 - epoxy - 3 - (7 - indenyloxy)propane and/or 1,2 - epoxy - 3 - (4indenyloxy)propane with the amine represented by formula III in a solvent such as one or more of water, methanol, ethanol, isopropanol, n-butanol,. tert-butanol, ethylene glycol, tetrahydrofuran or dioxane, in the presence of an alkali metallhydroxide such as sodium hydroxide or potassium hydroxide or an alkaline earth metal hydroxide such as barium hydroxide, or calcium hydroxide at room or higher temperatures. The product then obtained is a mixture of the 7-isomer and 4-isomer as described above since the product obtained equilibrates by tautomerism under the prevailing basic conditions.

The mixture of the acid addition salt of the 7-isomer and the acid addition salt of the 4isomer as obtained by adding an acid to the mixture prepared above has the unexpected property that the 4-isomer is isomerised into the 7-isomer by the presence of a small amount less than the stoichiometric amount of a base and only the acid addition salt of the 7-isomer is actually obtained, due to isomerisation within the mixture of the two isomers (free bases) obtained by the reaction. Such isomerisation can be effected on the reaction product mixture as it is, or after purification by adding thereto in an organic solvent an acid in an amount slightly less than the stoichiometric amount required to react therewith, the remaining free base itself then acting as the base, or by adding to the mixture of the isomers an acid in a stoichiometric amount or an amount slightly m excess of the stoicio- metric amount, to convert the whole isomeric mixture into acid addition salt and then adding a small amount of a basic material to the salt in an organic solvent. In the isomerisation reaction, it is unnecessary to dissolve the tautomeric mixture (free bases, acid addition salts) in a solvent. Purification of the mixture of the isomers can be performed by conventional methods such as, for example, filtration, concentration, extraction, distillation, column chromatography or recrystallisation.

Examples of the acid used for forming the acid addition salts of the isomers are, by way of illustration, organic acids such as citric, acetic, lactic, maleic, fumaric, benzoic, tartaric, ascorbic, succinic or malic acid, and inorganic acids such as hydrochloric, sulfuric, phosphoric or nitric acid. Illustrative examples of the basic materials used for the isomerisation are a free tautomeric mixture, and other organic and inorganic bases such as pyridine, triethylamine, sodium hydroxide or barium hydroxide.

Furthermore, after converting the aforesaid mixture of isomers into the mixture of the acid addition salts of the isomers by addition to the isomer mixture as it is or after purification of a stoichiometric or slightly excess amount of an acid then the acid addition salt of the 7isomer and the acid addition salt of the 4isomer can be separated and recovered by fractional recrystallisation. For the fractional recrystallisation, an organic solvent such as methanol and isopropanol is typically used.

The compound of this invention shows methamphetamine stereotyed increasing activity, which is one of the desired pharmacological properties for an antidepression agent, and further the observed activity is stronger than that of the known antidepressant agent, Amitriptyline.

The compound of this invention also has shown a stronger antireserpine activity than that of known compounds, which activity is one of the desired pharmacological properties for an antidepressant agent.

The acute toxicity of the compound of this invention upon oral administration is observed to be about 9 of the known compounds, and compound of this invention exhibit an excellent safety coefficient for medical treatment, considering the potential activities of the compound.

The compound of this invention further shows higher activity in potentiation of the effect of 5-hydroxytryptophan (which is one of the desirable effects for an antidepressant agent) compared with the known compounds Amitriptyrine and Imipramine.

Furthermore, rhe isolated 7-isomer acid addition salt shows better pharmacological activity than the 4-isomer acid addition salt.

The present invention therefore further provides a pharmaceutical composition comprising the novel compound together with pharmaceutically acceptable diluent.

The aforementioned activities of compound of the present invention are demonstrated by the following experiments: EXPERIMENT 1.

The effects of the compounds on methamphetamine-induced stereotyped behaviour in rats (male Wistar strain, age 8 weeks) were examined according to the method of Ueki el al. (Folia Pharmacologica Japonica, 68, 716 1972).

The rats were placed in separate plastics cages for 1 hour to be accustomed to the experimental conditions and then the compounds under test were given intraperitoneally followed by an intraperitoneal application after 1 hour of methamphetamine (5 mg/Kg). The influence of the compounds on the agitated behaviour of the rate was observed every 30 minutes till 5 hours thereafter.

The EDso of the compounds under test were 5.0 mg/Kg and 12.5 mg/lKg i.p. for 2 - (7 - indenyloxymethyl)morpholine hydrochloride and 2 - (4 - indenyloxymethyl)morpholine hydrochloride, respectively. The former was 2.5 times as potent as the latter.

EXPERIMENT 2.

The effects of the compounds on reserpineinduced hypothermia in mice (male ICR-JCL strain, age 5 weeks) was investigated by the method of Ueki et al. (ibid).

The mice were pretreated with reserpine (3 mgjKg s.c.) and housed in separate plastics cages for 17 hours. The room temperature was kept at 23 10 C. The compounds under test were given orally and the rectal temperature of the mice was measured 5 hours thereafter.

The differences of the rectal temperature (AT) in the rats compared to those of a control group, and the sum of the differences (OT), were calculated. Thereafter by graphical estimation of ED T= 1.50C, the ED T=!1.50C of 2 - (7 - indenyloxymethyl)morpholine hydrochloride and 2 - (4 - indenyloxymethyl)morpholine hydrochloride were 1.8 mg/Kg and 2.4 mg/Kg p.o., respectively. The former proved to be more potent than the latter in efficacy.

The following examples illustrate the present invention. The starting materials used in Examples 5 and 6 may be prepared by methods as described in the specification of the main invention.

Reference Example l(a).

In a mixed solution of 29 ml. of 70% sodium hydroxide solution and 35 g. of 2aminoethyl hydrogen sulfate (H2N CH2CH2OSO3H) was added 9.4 g. of 1-(7-indenyloxy)-2,3epoxypropane (containing about 35% 1-(4indenyloxy) - 2,3 - epoxypropane) dissolved in 50 ml. of methanol and the mixture was stirred for one hour at 55 lC. To the mixture was added 50 ml. of 70% sodium hydroxide and stirred for further 16 hours at 55"C. After cooling, 300 ml. of water was added to the reaction mixture and then the product was extracted thrice each with 100 ml. of toluene.

The extracts were combined, washed with water, dried, and then the residue was distilled. By collecting the fractions having boiling points of 146156,C./0.5 mm Hg, 6.7 g (yield 58.0%) of oily 2-(7-indenyloxymethyl)morpholine (containing 32% 2 (4 - indenyloxymethyl)morpholine) was obtained.

The proportions of the both isomers was measured by gas chromatography after trifluoroacetylation the isomer mixture with trifluoroacetic anhydride.

Elemental analysis for C14H1,NO2: C(%) H(%) N(%) Calculated: 72.70 7.411 6.06 Found: 72.91 7.50 5.95 Reference Example 1'(b).

In 30 ml. of acetone was dissolved 3 g. of the oily base obtained from Reference Example l(a), and after acidifying the solution thus obtained with isopropanol-hydrochloric acid, the solution was mixed with 50 ml. of ether. The mixture was allowed to stand overnight in an ice chamber at - 100C.

to precipitate crystals, which were recovered by filtration to provide 2.8 g. (yield 80.4%) of 2 - (7 - indenyloxymethyl)morpholine hydrochloride (containing 40% 2 - (4- indenyloxymethyl )morpholine hydrochloride) melting at 143-1550C.

The proportions of the both isomers in the product was measured by gas chromatography after trifluoroacetylating the product with trifluoroacetic anhydride.

Elemental analysis for Cl4Hl8NO2Cl: C(%) Hl(%) N(%) C1(%) Calculated: 62.80 6.78 5.23 13.24 Found: 62.84 6.81 5.24 13.01 Example 1.

In 70 ml. of acetone was dissolved 3 g. of the oily base obtained from Reference Example 1(a), the solution was weakly acidified by isopropanol-hydrochloric acid under ice-cooling and then allowed to stand overnight in a refrigerator. The crystals thus precipitated were recovered by filtration and washed with acetone and then ether to provide 1.1 g. of 2 - (4 - indenyloxymethyl)morpholine hydrochloride (containing 15% 2-(7-indenyloxymethyl)morpholine hydrochloride) showing melting point of 159-1630C. Then, by repeating the recrystallization from methanol, pure 2 - (4 - indenyloxymethyl)morpholine hydrochloride showing melting point of 175-1760C. was obtained.

Elemental analysis for :C14H1sNO,Cl N(%) Calculated: 5.23 Found: 531 Nuclear magnetic resonance spectra: (CDC13+lD6DMSO; ppm) 3.0-3.4 (4H, m,

4.0-4.1 (4H, m O~CH2,

4.3 (1H, m,

3.4 (2H,

6.5 (1H, doublet, J =6Hz)

7.0 (1H, doublet, J = 6 Hz)

6.8 (1H, q,

7.1 (2H, d,

The mother liquor and washings were combined, dried up under reduced pressure, and after adding thereto 50 ml. of toluene followed by drying again under reduced pressure, the residue obtained was dissolved once in 30 ml.

of acetone. The solution thus obtained was allowed to stand overnight at room temperature and the crystals thus formed were recovered by filtration and washed with acetone to provide 1.7 g. of 2z(7-indenyloxymethyl)- morpholine hydrochloride (containing 10% 4indenyloxy isomer) showing a melting point of 138-153 C. The proportions of the both isomers was measured by gas chromatography after trifluoroacetylating the product with trifluoroacetic anhydride. Then, by repeating the recrystallization from methanol, 1.7 g.

of pure 2 - (7 - indenyloxymethyl)morpholine hydrochloride having the following properties was obtained.

Elemental analysis for C14H18NO2Cl: N( / ) Calculated: 5.23 Found: 5.29 Nuclear magnetic resonance spectra: (CDCl,+D6-DMSO: ppm): 3.0-3.4 (4H, m,

4.04.2 (4H, m -02

4.3 (1H, m,

3.34 (2H,

6.58 (1H, doublet,

J=6 Hz) 6.84 (llH, doublet

J=6 Hz) 6.78 (H, d,

7.04 (1H, d,

7.20 (1H, t,

10.0 (2H,

Reference Example 2.

A mixture of 4.7 g. of a mixture of 1-(4- indenyloxy) - 2,3 - epoxypropane and 1 (7 - indenyloxy) - 2,3 - epoxypropane, 1-1.5 g.

of 2-chloroethylamine hydrochloride, 10 g. of sodium hydroxide, 100 ml. of ethanol, and 50 ml. of water was stirred for 24 hours at 60--650C. After cooling, the mixture was acidified by 5% hydrochloric acid and ethanol was distilled away under reduced pressure.

The resulted aqueous solution was washed with ethyl acetate, alkalified with an aqueous 5% sodium hydroxide solution, and then extracted thrice each with 50 ml. of ether. The extracts were combined and dried over anhydrous sodium sulfate and then ether was distilled away from the extract under reduced pressure. The oily material obtained was subjected to a silica gel chromatography and eluted by a solvent mixture of chloroform:methanol l(9:l) and from the eluate 500 mg. of a mixture of 2-(4-indenyloxymethy1)- morpholine and 2 - (7 - indenyloxymethyl)morpholine (the proportions of 7-indenyl isQmer:4-indenyl isomer was 17:8) was obtained.

The product obtained coincided completely with the product obtained in Reference Example ll(a).

Reference Example 3.

Into 10.6 ml. of pyridine was added 2.5 g.

of chlorosulfonic acid with stirring at 05 C and then 5.0 g. of a mixture of 14(4-indenyl- oxy) - 3 - , - hydroxyethylamino - 2- propanol and 1 - (7 - indenyloxy) - 3 hydroxyethylamino - 2 - propanol dissolved in 10 ml. of pyridine was added dropwise to the mixture. The reaction mixture was stirred for 3 hours at 250C. and then the solvent was distilled away under reduced pres sure. The oily material obtained was added to a solution consisting of 2.4 g. of sodium hydroxide, 13 ml. of water, and 26.4 ml. of ethanol and refluxed for 24 hours.

After cooling the reaction mixture, ethanol was distilled away under reduced pressure, 50 ml. of water was added to the residue, and the mixture was extracted thrice each with 50 ml. of ether. The extracts were combined, dried over anhydrous sodium sulfate, and then ether was distilled away under reduced pressure. The residue formed was subjected to silica gel column chromatography and eluted by a solution mixture of chloroform and methanol (9:1). From the eluate, 1.1 g. of a mixture of 2 (4-indenyloxym.ethyl)- morpholine and 2 - (7 - indenyloymethyl)- morpholine (the proportions of the 7-indenyl compound and the 4-indenyl compound was 17:8) was obtained. The product obtained coincided completely with that of obtained in Reference Example 1(a).

Example 2.

In 20 ml. of acetone was suspended 10 g.

of a mixture (3:7) of 2-(4-indenyloxymethyl)- morpholine hydrochloride and 2 - (7indenyloxymethyl) morpholine hydrochloride and after adding to the suspension 3 g. of a mixture (3:7) of 2 - (4 - indenyloxy- methyl)morpholine and 2 - (7 - indenyl- oxymethyl)morpholine, the resultant mixture was stirred for 24 hours at room temperature. The crystals thus precipitated were recovered by filtration, thoroughly washed with acetone, and 10 g. of the crude crystals recovered were recrystallized from 40 ml. of methanol to provide 7.0 g. of 2-(7-indenyl- oxymethyl)morpholine hydrochloride.

Elemental analysis for C14H18O2NCl: C(%) H(%) N(%) Cl(%) Calculated: 62.80 6.78 5.23 13.24 Found: 63.01 6.75 5.11 )12.98 Nuclear magnetic resonance spectra (cDCl8+D6-DMSO): 8 (ppm): 3.0-3.4 (m, 4H,

4.0-4.2 (m, 4H, wCE2

4.3 (m, lH,

3.34 (2H,

6.58 (doublet, 1H,

J=6 Hz) 6.84 (doublet, 1H, JI 6 Hz)

6.78 (d, 1H;

7.04 (d, 1H,

7.20 (t, 1H,

Example 3.

In 20 runt. of jsopropyl alcohol was dissolved a mixture of 10 g. (0.043 mol) (3:7) of 2 (4 - indenyXoxyrn thyl)morpholine and 2 (7 - indenyIoxymetfyl)morpholine and after adding to the solution 5.9 ml. (0.032 mol) of 20% w/v hydrogen chloride in isopropyl alcohol, the rnixture was, stirred for 24 hours at room temperature. The crystals thus precipitated were recovered by filtration, thoroughly washed with acetone, an,d then recrystallized from 40 ml of methanol to provide 7.7 g. of 2-(7-indenyloxymethyl)mor- pholine hydrochloride.

Elemental analysis for C14H18O2NCl: C(%) H(%) N(%) Cl(%) Calculated: 62.80 6.78 5.23 13.24 Found: 62.54 6.63 5.08 13.00 Example 4.

In 20 ml. of methanol was suspended 10 g.

Of a mixture (3:7) of 2-(4-lndeny, oxymethyl) morpholine hydrochloride and 2 - (7indenyloxymethyl ) morpholine hydrochloride and after adding to the suspension 0.3 g. of triethylamine, the mixture was stirred for 24 hours at room temperature. The crystals thus precipitated were recovered by filtration, thoroughly washed with acetone, and recrystallized from 40 ml. of methanol to provide 6.3 g. of 2 - (7 - indenyloxymethyl)morpholine hydrochloride.

Elemental analysis for C14H18O2NCl: O(%) H(%) N(%) Cl(%) Calculated: 62.80 6.78 5.23 13.24 Found: 62.77 6.83 5.40 13.29 Example 5.

In 500 ml. of ethanolic hydrochloric acid (350 ml. of 0.5 N hydrochloric acid and 150 ml. of ethanol) was dissolved 5.0 g. of 4-triphenylmethyl - 2 - (1 - hydroxy - 4 - indanyloxymethyl)morpholine and the solution was refluxed 17 hours. After cooling the reaction mixture, ethanol was distilled away under reduced pressure until the whole volume of the reaction mixture became about 350 ml: Sodium chloride was added to the reaction mixture to cause salting out and the mixture was extracted thrice each with 200 ml. of chloroform. The chloroform extracts were combined, dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. Then, by adding acetone to the syrupy residue formed, 2.0 g.

of 2 - (7 - indenyloxyrnethylBmorpholine hydrochloride was obtained as precipitates.

Melting point of the hydrochloride: 155-156 C.

Melting point of the maleate: 154-156 C.

Elemental analysis for C14H18NO2Cl: C(%) H(%) N(%) Cl(%) Calculated: 62.75 6.78 5.23 13.24 Found: 62.81 6.79 5.40 13.11 Nuclear magnetic resonance spectra CDCl3+D6-DMSO): 8 (ppm) 3.0-3.4 (m, 4H,

4.04.2 (m, 411,

4.3 (m, 1H,

3.34 (2H,

6.58 (doublet, 1.H

J=6Hz) 6.84 (doublet, 1R

J=6 Hz) 6.78 (d, 1H,

7.04 (d, H,

7.20 (t, 1H,

10.0

Example 6.

To 1.0 g. of 2-(1-hydroxy-4-indanyloxy- methyl)morpholine were added 50 ml. of ethanol and 50 ml. of 0.5 N hydrochloric acid and the mixture was re fluxed for 17 hours. After cooling, the reaction mixture was concentrated under re duced pressure until the whole volume became about 50 ml and then sodium chloride was added thereto to cause salting out. The reaction mixture was extracted thrice each with 50 ml. of chloroform. The extracts were combined, dried over anhydrous magnesium sul fate, and the solvent was distilled away. The syrupy residue formed was dissolved in a - small amount of isopropyl alcohol and then acetone was added to the solution to provide 830 mg. of light yellow powder of 2-(7 indenyloxymethyl ) morpholine hydrochloride as the precipitates.

By recrystallizing the product from acetone, the colorless acicular crystals of the aimed compound having melting point of 155-156 C were obtained.

Elemental analysis for C14H18NO2Cl: C(%) H(%) N(%) C1!(%) Calculated: 62.75 6.78 5.23 1324 Found: 63.43 6.72 5.43 12.91 Nuclear magnetic resonance spectra (CDCl8+D6-DMSO) 3 (ppm): 3.0-3.4 (m, 4H

4.0-42 (m, 4H,

4.3 (m, 1H,

3.34 (2H,

6.58 (doublet, 1H

J=6Hz) 6.84 (doublet, 1H,

J=6Hz) 6.78 (d, 1,

7.04 (d, 1H

7.20 (t, 1H,

10.0

WHAT WE CLAIM 'IS:- 1. IAn acid addition salt of 2 < (7-indenyloxy- methyl)morpholine represented by the general formula

2. A process for producing an acid addition salt of 2 - (7 - indenyloxymethyl)morpholine according to claim 1 which comprises reacting at least one of 1,2 - epoxy - 3 - (7indenyloxy)propane and 1,2 - epoxy - 3 (4 - indenyloxy)propane, represented by the general formula

wherein one of the dotted lines represents a single bond and the other represents a double bond, with an amine represented by the general formula H2'N-CH2CH2Z wherein Z represents a halogen atom or -OSO,R4 (wherein R4 represents a hydrogen atom, an aryl group or a lower alkyl group) in the presence of base to f

Claims (1)

1. **WARNING** start of CLMS field may overlap end of DESC **.

   6.78 (d, 1,

   7.04 (d, 1H

   7.20 (t, 1H,

   10.0

   WHAT WE CLAIM 'IS:-

   1. IAn acid addition salt of 2 < (7-indenyloxy- methyl)morpholine represented by the general formula

   2. A process for producing an acid addition salt of 2 - (7 - indenyloxymethyl)morpholine according to claim 1 which comprises reacting at least one of 1,2 - epoxy - 3 - (7indenyloxy)propane and 1,2 - epoxy - 3 (4 - indenyloxy)propane, represented by the general formula

   wherein one of the dotted lines represents a single bond and the other represents a double bond, with an amine represented by the general formula H2'N-CH2CH2Z wherein Z represents a halogen atom or -OSO,R4 (wherein R4 represents a hydrogen atom, an aryl group or a lower alkyl group) in the presence of base to form a mixture of the 2 - (7 - indenyloxymethyl)morpholine and the 2 - (4 - indenyloxymethyl)morpholine, represented by the general formula

   wherein the dotted lines have the same significance as defined above, and adding to the mixture an acid in an amount less than the stoichiometric amount to isomerise the 2-(4indenyloxymethyl ) morpholine.

   3. tA process for producing an acid addition salt of 2 - (7 - indenyloxymethyl)morpholine according to claim 1 which comprises adding to a mixture of the 2-i(7-indenyloxymethyl)morpholine and the 2 - (4 indenyloxymethyl) morpholine, represented by the general formula

   wherein one of the dotted lines represents a single bond and the other represents a double bond, an acid in an amount less than the stoichiometric amount to isomerise the 2-(4indenyloxymethyl )morpholine.

   4. A process for producing an acid addition salt of a 2~l(7-indenyloxymethyl)morpholine according to claim 1 which comprises adding to a mixture of the acid addition salts of the 2 - (7 - indenyloxymethyl)morpholine and the 2 - (4 - indenyloxymethyl)morpholine, represented by the general formula

   wherein one of the dotted lines represents single bond and the other represents double bond, less than the stoichiometric amount of base to isomerise the 2-(4-indenyloxymethyl)morpholine.

   5. A process for preparing an acid addition salt of 2 - (7 - indenyloxymethyl) morpholine, substantially as described in any one of the Examples.

   6. An acid addition salt of 2-(7-indenyloxy- methyl)morpholine when prepared by a process according to any one of claims 2 to 5.

   7. A pharmaceutical composition compris

   ing an acid addition salt of a 2-(7-indenyloxymethyl)morpholine according to claim 1 or claim 6 together with a pharmaceutically acceptable diluent.