RU2123496C1 - Morpholine derivative or its pharmaceutically acceptable salt and pharmaceutical composition based on thereof - Google Patents

Abstract

FIELD: organic chemistry, pharmacy. SUBSTANCE: invention relates to chemistry of heterocyclic compounds showing antagonism with respect to 5-HT₂-receptors and activity inhibiting reuptake of 5-HT. Invention relates to derivative of morpholine of the formula (I)

where R¹ and R³ are similar or distinct and each means hydrogen atom or lower alkyl-group; R² is halogen atom and dotted line means optionally double bond, or its pharmaceutically acceptable salts, and pharmaceutical composition based on thereof. These compounds can be used for synthesis of antidepressive and sedative drugs. EFFECT: improved method of synthesis. 7 cl, 4 tbl

Description

Technical field
This invention relates to a derivative of morpholine or a salt thereof having antidepressant activity and a calming effect.

BACKGROUND OF THE INVENTION
The involvement of serotonin (hereinafter referred to as 5-HT) in the antidepressant action has been reported [Norio Ogawa (ed), Shinnonoreseputa, Sekai Hoken Trushinsha (1991, etc)], and studies have been directed at inhibiting 5-HT reassimilation or affecting 5- receptors NT.

 Tricyclic compounds, such as amitriptyline, are widely used clinically as antidepressants.

 Although amitriptyline has 5-HT reassimilation inhibitory activity or 5-HT receptor antagonistic activity, it additionally has norepinephrine reassimilation inhibitory activity and anticholine activity and is indiscriminate, and therefore it is believed to cause side effects in cardiac circulatory system (e.g., palpitations), thirst, urinary retention, etc.

Therefore, it is desirable that drugs that selectively inhibit 5-HT reassimilation or selectively act on 5-HT ₂ receptors have reduced side effects. Clinically used 5-HT reassimilation drugs that have been used clinically include, for example, fluoxetine. However, fluoxetine has been reported to cause anxiety or insomnia during the course of treatment [Physician's Desk Reference, Medical Economics Company, Oradell, N 7 (1990)].

Medicines that are selective 5-HT ₂ receptor antagonists include, for example, mianserin, which is known as an antidepressant.

Recent various studies have highlighted the need for a compound having selective inhibitory activity for the reassimilation of 5-HT along with selective antagonistic activity for the 5-HT ₂ receptor [Cell Biology to Pharmacology and Therapeutics, 488-504 (1990), Psychopathology, 22 ( Suppl. 1), 22-36 (1989), J. Chin. Psychiatry, 52, 34-38 (1991), Psychopharmacol Bill, 26, 168-171 (1990) and Br.Pharmacolo., 100, 793-799 (1990)].

Medicines having both 5-HT reassimilation inhibitory activity and 5-HT ₂ receptor antagonistic activity include, for example, trazodone. However, the inhibitory reassimilation of 5-HT activity of trazodone is very weak, and the antidepressant activity and the calming activity of trazodone have been reported to be based on its antagonism of 5-HT ₂ receptors [Marek GJ, et al., Psychopharmacology, 109, 2-11 (1992) ].

Further, in addition to the two above-mentioned activities, trazodone is also effective against d ₁ receptors and therefore causes side effects based on this feature.

 JP-A-46-7333 (the term “JP-A” refers to an unexamined published Japanese patent application) describes 2 - [[(4-indanyl) oxy] methyl] morpholine and JP-A-52-83773 describes 2 - [[ (7-indenyl) oxy] methyl] morpholine. However, these compounds do not have a substituent on the indanyloxy group or on the indenyloxy group.

 Description of the present invention.

 This invention relates to a morpholine derivative, which is structurally characterized by the presence of a halogen atom in the benzene ring of an indanyloxy group or indenyloxy group and, therefore, is completely different in chemical structure from ordinary compounds.

The morpholine derivative of the present invention exhibits selective 5-HT activity inhibiting reassimilation and selective 5-HT ₂ receptor antagonistic activity, and both activities have excellent effects.

 The aim of this invention is to provide a new derivative of morpholine represented by formula I, shown below, or its salt.

Another objective of the present invention is the development of a medicament having selective inhibitory reassimilation of 5-HT activity together with selective antagonistic activity against 5-HT ₂ receptors, which contains as an active ingredient the compound I of this invention or its salt, and the development of a pharmaceutical composition, containing compound I according to this invention and or its salt and a pharmaceutically acceptable carrier.

 This invention includes a compound represented by formula II below, which is included in compound I of the present invention, or a salt thereof, and therefore a further object of the present invention is to provide a compound (II).

где R¹ и R³, которые могут быть одинаковыми или различными, каждый обозначает атом водорода или низшую алкильную группу;
R² обозначает атом галогена;
пунктирная линия может указывать на необязательную двойную связь.1) The morpholine derivative represented by formula I and its salt:

where R ¹ and R ³ , which may be the same or different, each represents a hydrogen atom or a lower alkyl group;
R ² represents a halogen atom;
the dashed line may indicate an optional double bond.

или его соль
где R¹ и R³, которые могут быть одинаковыми или различными, каждый обозначает атом водорода или низшую алкильную группу;
R² обозначает атом галогена.2) A morpholine derivative represented by formula II,

or its salt
where R ¹ and R ³ , which may be the same or different, each represents a hydrogen atom or a lower alkyl group;
R ² represents a halogen atom.

 The compounds of this invention are described in more detail below. Unless otherwise indicated, the terminology "lower" is used for general formulas when designating a straight or branched carbon chain containing from 1 to 6 carbon atoms.

 Specific examples of the “lower alkyl group” are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3- dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl.

 A lower alkyl group having from 1 to 3 carbon atoms, such as methyl, ethyl, propyl or isopropyl, is preferred.

 A “halogen atom” includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, with a fluorine atom being preferred.

 The dashed line implies that the indan ring may have a double bond.

I
являются каждая из следующих формул:

где символы указаны выше, или смесь соединений (a) и (b).That is, in accordance with this value of the dashed line, examples of the structure of formula I:

I
are each of the following formulas:

where the symbols are indicated above, or a mixture of compounds (a) and (b).

 Depending on position 2 of the morphic group or type of substituent, the compounds of this invention include stereoisomers, such as optical isomers based on an asymmetric carbon atom, and geometric isomers.

 The present invention includes all of these isomers, either as a mixture or separately. Preferred isomers of compounds I and II or their salts are levorotatory optical isomers.

 Compounds I and II can form salts with acids. Such salts include salts with inorganic acids, for example, mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; or with organic acids, such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, D-dibenzoyl tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid and glutamic acid. Hydrochlorides, oxalates, fumarates and D-benzoyl tartrates are preferred.

 The compounds of the present invention can form hydrates and various solvates or exhibit polymorphism.

 The method of obtaining.

 The compounds of the present invention can be obtained using the following methods, which, however, do not limit the methods for their preparation.

 The way.

где
R² указано выше;
R^1' обозначает атом водорода, низшую алкильную или кетоновую группу;
X обозначает аминозащитную группу;
Y обозначает атом галогена, мезилоксигруппу или тозилоксигруппу.

Where
R ^{2 is} indicated above;
R ^{1 ′} represents a hydrogen atom, a lower alkyl or ketone group;
X is an amino protecting group;
Y represents a halogen atom, a mesyloxy group or a tosyloxy group.

 An amino protecting group is a commonly used protecting group and includes a trityl, benzhydryl, p-methoxybenzyl and tert-butyl group, with a trityl group being preferred.

 The above reaction is carried out by mixing the morpholine derivative (III) and the indanol derivative (IV) in an appropriate ratio in an inert solvent in the presence of a base at room temperature or by heating, or the indanol derivative (IV) is first converted to its sodium or potassium salt and then subjected interaction with a derivative of morpholine (III) in an inert solvent at room temperature or by heating (stage 1). The protective group of the product is cleaved off in the usual way, for example, by reduction (e.g., catalytic reduction, reduction with liquid ammonia, etc.) or by treatment with an acid to give compound (V) of the present invention (step 2). The inert solvent used in step 1 includes benzene, chloroform, dimethylformamide (hereinafter abbreviated as DMF), dimethyl sulfoxide (hereinafter abbreviated as DMSO), ethyl ether, water, methanol and ethanol. The base used in step 1 includes sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, lithium hydride, sodium carbonate, potassium carbonate, butyl lithium and potassium tert-butoxide. The acid used in step 2 includes acetic acid, trifluoroacetic acid, trichloroacetic acid, hydrochloric acid, sulfuric acid, and hydrobromic acetic acid.

 The deprotection reaction is usually carried out in an inert solvent, such as methanol, ethanol or acetone, or in water at room temperature or under heating (when refluxed).

 Method 2

где
R¹, R², Y и пунктирная линия указаны выше.

Where
R ¹ , R ² , Y and the dashed line are indicated above.

 Stage 1. Synthesis of halogen-4-indanyl (or indenyl) glycidyl ether.

Halogen-4-indanyl (or indenyl) glycidyl ether (VIII) can be synthesized by reacting an indanol derivative (or indenol) (VI) and a propylene oxide derivative (VII) in a solvent such as water, acetone or acetonitrile in the presence of a base such as hydroxide sodium, potassium hydroxide or potassium carbonate, under conditions of from 0 ^o C to boiling under reflux.

 Stage 2. Synthesis of 2 - [[halogen-4-indanyl (or indenyl) oxy] methyl] -morpholine.

2 - [[(Halogen-4-indanyl (or indenyl) oxy] methyl] morpholine (X) can be synthesized by reacting halogen-4-indanyl (or indenyl) glycidyl ether (VIII) and aminoethylsulfuric acid (IX) in a mixed solvent such as water — methanol or water — ethanol, in the presence of a base, such as sodium hydroxide or potassium hydroxide, under conditions of 0 ^° C. to reflux.

 Thus obtained compound (X) according to this invention can be converted into a salt with an acid such as hydrochloric acid, fumaric acid, succinic acid, oxalic acid, D-dibenzoyl tartaric acid, etc.

 According to methods 1 and 2, which use the optically active compound of morpholine (III) or the optically active derivative of propylene oxide (VII), the corresponding optically active 2 - [[(halogen-4-indanyl (or indenyl)) oxy] methyl] can be obtained morpholine.

 The compound obtained according to methods 1 to 5 can be purified to increase optical purity by recrystallization using D-dibenzoyl tartaric acid, D-ditoluoyl tartaric acid, D-tartaric acid, etc. as separating agents and mixtures of acetonitrile-water, methanol, dimethylformamide, etc. as a recrystallization solvent.

 Method 3

где
R¹, R² и пунктирная линия имеют указанное выше значение;
R⁴ обозначает низшую алкильную группу;
Z обозначает атом галогена, арилсульфонилоксигруппу, низшую алкилсульфонилоксигруппу или алкилсульфатную группу.

Where
R ¹ , R ² and the dashed line are as defined above;
R ⁴ is a lower alkyl group;
Z is a halogen atom, an arylsulfonyloxy group, a lower alkylsulfonyloxy group or an alkyl sulfate group.

 An arylsulfonyloxy group includes a phenylsulfonyloxy group and a p-toluenesulfonyloxy group; a lower alkylsulfonyloxy group includes a methylsulfonyloxy group, an ethylsulfonyloxy group and a propylsulfonyloxy group; and the alkyl sulfate group includes a methyl sulfate group, an ethyl sulfate group and a propyl sulfate group.

 The compounds of this invention can be obtained by N-alkylation in the usual way.

 N-alkylation is carried out by reacting an unsubstituted derivative of morpholine (X) with an appropriate reaction amount of an alkylating agent (XI) in an inert solvent such as acetone, acetonitrile, tetrahydrofuran (hereinafter abbreviated as THF), ethyl ether or DMF, in the presence of a base such as potassium carbonate , sodium hydride or potassium hydride, at room temperature or at elevated temperature (or when boiling under reflux).

 (Alternative way).

 Alternatively, N-alkylation can be carried out by stirring an unsubstituted derivative of morpholine (X) in the presence of an appropriate reaction amount of lower alkyl aldehyde and sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, etc. in an inert solvent such as methanol, ethanol, THF or dioxane, at room temperature or at elevated temperature. This interaction is preferably carried out in an acidic environment with the addition of hydrochloric acid, acetic acid, formic acid, etc.

 Method 4

где
R², X и пунктирная линия указаны выше;
R⁵ обозначает низшую алкильную группу.

Where
R ² , X and the dashed line are indicated above;
R ⁵ represents a lower alkyl group.

The lower alkyl group in the form of R ⁵ is indicated above and is preferably a methyl or ethyl group.

 Derived Eden (XVII) according to this invention can be obtained using the following stages.

 Stage 1

 Stage 1 is based on conventional recovery. Typical interaction methods are shown below.

 Process A.

 The ketone derivative (XIII) is reacted with an appropriate reaction amount of a reducing agent (e.g., borate, alan, sodium tetrahydroborate, lithium tetrahydroborate, lithium tetrahydroaluminate, sodium triacetoxyborohydride, diisobutylaluminum hydride or sodium cyanoborate in an inert solvent such as lower methanol, such as low alcohol, for example or propanol), diethyl ether, THF, benzene, toluene, dichloroethane, chloroform or water) under / from cooling to boiling under reflux to obtain hydroxyproi Water (XIV).

 Method B (catalytic reduction).

 The ketone derivative (XIII) is mixed with a metal catalyst (e.g. Raney nickel, nickel tetroxide or dichloromedy) in an alcohol such as methanol or ethanol at / from room temperature to heat.

Method C:
The ketone compound (XIII) and the corresponding reaction amount of dithionite (e.g. sodium dithionite) are mixed in a mixed solvent such as DMF-water, THF-water, dioxane-water, methanol-water or ethanol-water, with cooling or at room temperature.

 Stage 2

 The reaction is carried out by mixing the hydroxy derivative (XIV) in alcohol (XV), such as methanol or ethanol, in an acidic medium with hydrochloric acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, sulfuric acid or hydrobromic acid - acetic acid, at room temperature or when heated .

 Stage 3.

 The reaction is carried out by stirring the alkoxy compound (XVI) obtained in stage 2 in an inert solvent such as toluene, benzene, THF or 1,4-dioxane, in the presence of an acid catalyst (e.g. hydrochloric acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid or acetic acid) at room temperature or when heated.

 Derivative 2 - [[(halogen-4-indenyl) oxy] methyl] morpholine or derivative 2 - [[(halogen-7-indenyl) oxy] methyl] morpholine obtained according to methods 1 to 4, in some cases partially isomerized with ease at room temperature, giving an isomeric mixture with a ratio of approximately 1: 1.

 This mixture can be separated into individual isomers by converting this compound into salt using a conventional salt forming reaction, followed by separation, for example, by recrystallization.

 Method 5

где
R² и X имеют значения, указанные выше.

Where
R ² and X are as defined above.

 This method relates to the preparation of compound (XIX) according to this invention, in which the 3-position of the indane ring is substituted with a methyl group.

 Stage 1

 The reaction is carried out by reacting a ketone derivative (XIII) and an appropriate reaction amount of a methylating agent, such as an organometallic reagent (e.g. methyl lithium, Grignard reagent, methyl halide, trimethyl aluminum, methyl copper or dimethyl copper), in an anhydrous solvent such as THF, diethyl ether, benzene, toluene, dichloromethane or 1,4-dioxane, with cooling or at room temperature.

According to a preferred reaction method, the ketone derivative (XIII) and the corresponding reaction amount of methyl lithium or methyl magnesium bromide are stirred in THF or diethyl ether under cooling or at room temperature, for example, from -78 to 0 ^° C.

 Method A.

 The hydroxymethyl derivative (XVIII) obtained in step 1 is catalytically reduced in the usual manner. Typically, the reaction is carried out by stirring compound (XVIII) in an inert solvent, such as a lower alcohol (e.g. methanol, ethanol or propanol), THF, 1,4-dioxane, diethyl ether, ethyl acetate, benzene, toluene or dichloromethane, in the presence of a metal a catalyst (e.g., palladium-on-charcoal, dihydroxypalladium or platinum dioxide) in a hydrogen atmosphere under cooling or at room temperature.

 Method B.

 The hydroxymethyl derivative (XVIII) obtained in Step 1 and the corresponding reaction amount of trialkylsilane (e.g. trimethylsilane or triethylsilane) are mixed in an inert solvent such as methanol, ethanol, THF, dioxane, diethyl ether or acetonitrile, in the presence of an acid such as acetic acid, trifluoroacetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid, with ice cooling or at room temperature.

 (Method alternative to method 5).

где
R² и X указаны выше.

Where
R ² and X are indicated above.

The reaction is carried out by subjecting the ketone derivative (XIII) to the usual Wittig reaction using the Wittig reagent (for example, CH ₂ PPh ₃ ) in a well-known manner [Shin Jikken Kagaku Koza 14 (1), 224 - 238, Maruzen KK (1977)], obtaining exo- methylene derivative (XX) (stage 1). The exomethylene derivative obtained in step 1 is then reduced in the usual manner [Reductions in Organic Chemistry, Ellis Worwood Ltd. (1984)].

 Industrial applicability.

The compound of the present invention inhibits the reassimilation of 5-HT with high selectivity, and also exhibits selective antagonism of 5-HT ₂ receptors. Therefore, this compound is applicable as a therapeutic agent for the treatment of depression, anxiety, psychosomatic diseases, impaired autonomic regulation or anxiety with reduced side effects, and as a therapeutic agent for the treatment of critical manifestations associated with cerebrovascular disorders or Alzheimer's disease, such as decreased spontaneity, dysthymia , anxiety and impatience, hallucinations and illusions, hypochondria, sleep disturbance, etc. Further, the compound of the present invention has an antireserpine action that improves viscosity by blood, has an antihypoxic effect, is an antioxidant and is applicable as a means for cerebral blood supply and metabolic improvement or as a means for improving brain function, and also as an analgesic. In addition, the compound of the present invention can be used to treat cerebral dysfunction or dementia (dementia) accompanying Alzheimer's disease.

The following describes in detail a study of the inhibition of 5-HT reassimilation and a study of antagonism with respect to the 5-HT ₂ receptor to demonstrate the effects of the compounds of the present invention.

 1) Inhibition study of 5-HT reassimilation.

 In vitro study.

5-HT inhibitory reassimilation activity is investigated by examining the degree of inhibition of [ ³ H] -citalopram binding by the test compound to 5-HT reassimilation sites.

Use the method of D'amato RJ et al. Described in J. Pharmacol. Exp. Ther. 242, 364 (1987). A buffer solution (0.5 ml) containing approximately 1.0 nM [ ³ H] -citalopram, a rat brain cortex membrane preparation (approximately 0.4 mg protein), and the test compound were allowed to interact at 25 ^° C. for 60 minutes . After this, the labeled ligand of the bound form is separated from the labeled ligand of the free form by suction filtration. The amount of ligand bound non-specifically to 5-HT reassimilation sites, which is obtained by adding excess unlabeled fluoxetine (10 μM), is subtracted from the total amount of bound ligand to obtain the amount of ligand specifically bound to 5-HT reassimilation sites. An IC ₅₀ (a concentration that reduces the amount of specifically bound ligand by 50%) is calculated for each compound and converted to a dissociation constant (K _i value).

 In vivo study.

The enhanced effects of L-5-hydroxytryptophan, which is the precursor of 5-HT, are studied [Naunyn-Schmiedeberg's Archives of Pharmacology, 311, 185-192 (1980)]. Male ICR mice weighing 30-40 g were used. The test drug was administered intraperitoneally and, after 30 minutes, 90 mg / kg L-5-hydroxytryptophan was intravenously injected. 5 minutes after the injection, animals were observed for 5 minutes with respect to tremor, shaking of the head and abduction of the hind limbs. The studied drugs were evaluated by ED ₅₀ in the manifestation of each action.

 2) Test for selectivity in inhibiting the reassimilation of 5-HT.

The degree of inhibition by the test compound of the absorption of [ ³ H] -5-HT, [ ³ H] -noradrenaline and [ ³ H] -dopamine into synaptosomes is determined. The Harada and Maeno method described in Biochem is used. Pharmacol., 28, 2645 (1979). Male Wistar rats are decapitated and removed from the cerebral cortex and striatum (corpus striatum). The cortex synaptosome fraction is prepared for uptake of 5-HT and norepinephrine, and the striatal synaptosome fraction is prepared for dopamine uptake.

Each synaptosome fraction was incubated at 37 ^° C. for 3 minutes and [ ³ H] -5-HT, [ ³ H] -noradrenaline and [ ³ H] -dopamine (10 ^-7 M) were added to the appropriate fractions. After further incubation for 2 minutes, the system is cooled with ice (0 ^° C.) to stop the reaction. The reaction system is then filtered through Whatman CF / B glass filters and the radioactivity trapped on the filters is measured in a liquid scintillation counter. Non-specific activity is obtained using a drug-free reaction system incubated at 0 ^° C. The test drug is evaluated by IC ₅₀ (concentration at which the absorption of each radioactive ligand is reduced by 50%).

3) Antagonism test for 5-HT ₂ receptors (in vitro).

The degree of inhibition of [ ³ H] -Ketanserin binding by the test compound is determined. Use the method of Legsen JE et al., Described in Mol. Pharmacol., 21, 301 (1982). A buffer solution (0.5 ml total) containing approximately 1.0 nM [ ³ H] -Ketanserin, a membrane preparation of rat cerebral cortex (approximately 0.2 mg protein), and a test compound were allowed to interact at 25 ^° C within 30 minutes. After this, the bound labeled ligand is separated by suction filtration. The amount of ligand bound non-specifically to 5-HT ₂ receptors, which is obtained by adding excess unlabeled Matergoline (10 μM), is subtracted from the total amount of bound ligand to obtain the amount of ligand bound specifically to 5-HT ₂ receptors. C ₅₀ (the concentration at which the amount of specifically bound ligand is reduced by 50%) is calculated for each compound and converted to a dissociation constant (K value).

(Test results)
The studies described above show that the compound of the present invention has both 5-HT reassimilation inhibitory activity and 5-HT ₂ receptor antagonistic activity in vitro, and both activities have excellent effects. In contrast, the compared compounds show very weak antagonism with respect to the 5-HT ₂ receptor, exhibiting 5-HT inhibitory reassimilation activity (see Table 1).

Further, in an in vivo test for inhibiting the reassimilation of 5-HT ED ₅₀ compounds, for example, example 4, in the manifestation of tremor, shaking of the head and abduction of the hind legs, is 6.3 mg / kg, 7.2 mg / kg and 14.1 mg / kg, respectively, indicating a strong inhibitory activity against reassimilation (re-inclusion) of 5-HT.

In the test for the selective inhibition of reassimilation of 5-HT IC ₅₀ for the compound, for example, Example 1, in the inhibition of the absorption of [ ³ H] -5-HT, [ ³ H] -noradrenaline and the absorption of [ ³ H] -dopamine is 227 nM, 6722 nM and 10,000 nM or more, respectively. These results show that the inhibitory absorption of [ ³ H] -5-HT activity of the compound of Example 1 is approximately 30 times or more higher than the inhibitory absorption of [ ³ H] -noradrenaline activity, and the inhibitory absorption of [ ³ H] -dopamine activity therefore shows 5-HT uptake selectivity.

 Accordingly, it can be expected that the compound of the present invention will not cause the side effects observed with compounds having non-selective absorption inhibiting activities, for example, side effects on the cardiovascular system (e.g., heart palpitations), and other side effects such like thirst and urinary retention.

 Preparations containing at least one of the compounds of the present invention or its salt as an active ingredient can be prepared using carriers, excipients and other additives used in pharmaceutical preparations.

 The carriers or excipients used in the preparations may be solid or liquid carriers, including lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, Arabian gum (gum arabic), olive oil, sesame oil, cocoa butter, ethylene glycol and others commonly used.

 The compounds of the present invention can be administered orally in the dosage form of tablets, pills, capsules, granules, powders, liquids, etc. or parenterally in the dosage form of an injection, for example, for intravenous or intramuscular administration, suppositories or preparations for transdermal administration.

 Usually the dose is in the range from 1 to 1000 mg, preferably 10-300 mg, per day for adults, usually given in a single dose or in several divided doses, which vary depending on the age, body weight and condition of the patients, therapeutic effect, period of treatment, route of administration, etc. It goes without saying that lower doses may be sufficient in some cases, as the dose may vary depending on different conditions, as mentioned above.

 The best embodiment of the present invention.

 Further, the present invention will be illustrated in more detail by examples, but it should be noted that the invention is not limited to these examples.

 The preparation of the starting compounds used in the examples is explained in the reference examples.

 The chemical structures obtained in the examples of the compounds are shown in table. 2-4.

 Reference example 1.

(i) Aminoethyl sulfate (423.6 g, 3.00 mol) is dissolved in a 70% aqueous sodium hydroxide solution (360 ml) and a methanol solution (400 ml) of allyl glycidyl ether (68.4 mg, 0.60 mol) is added to it. dropwise at 50 ^° C. After stirring the mixture at this temperature for 1 hour, a 70% aqueous solution of sodium hydroxide (600 ml) was added thereto, followed by stirring at the same temperature for 13 hours.

 After completion of the reaction, water was added to the reaction mixture at room temperature, and the mixture was extracted with chloroform (6 x 1000 ml). The extract was washed with an aqueous solution of sodium chloride (2 x 200 ml) and dried over magnesium sulfate. The solvent was removed by evaporation, and the residue was distilled under reduced pressure to obtain 2- (allyloxymethyl) morpholine (75.2 g) as a colorless oily substance.

Physiochemical properties:
¹ H-NMR (CDCl ₃ ) δ:
(2.65 dd, J = 10.3 Hz, J = 12.2 Hz, 1H), 2.74-2.93 (m, 3H), 3.36-3.49 (M, 2H), 3 , 59-3.70 (m, 2H), 3.90 (dd, J = 1.9 Hz, J = 11.7 Hz, 1H), 4.01 (dd, J = 0.96 Hz, 5, 84 Hz, 9H), 5.17-5.25 (m, 1H, 11-H), 5.28-5.30 (m, 1H, 11-H), 5.86-5.96 (m, 1H, 10-H)
MS (GC / MS): m / z 157 (M ⁺ )
(ii) 2- (allyloxymethyl) morpholine (39.5 g, 0.25 mol) was dissolved in 1,4-dioxane (500 ml) and potassium tertbutoxide (28.2 g, 0.25 mol) was added to the solution at room temperature followed by refluxing for 3 hours. After completion of the reaction, water was added to the reaction mixture at room temperature, and the reaction mixture was extracted with chloroform (3 x 1000 ml). The extract was washed with a saturated aqueous solution of sodium chloride (1000 ml) and dried over magnesium sulfate. The solvent was removed to give 2- (1-propenyl-hydroxymethyl) morpholine (40.0 g) as a pale yellow oily substance.

Physiochemical properties:
¹ H-NMR (CDCl ₃ ) δ:
1.58 (dd, J = 1.80 Hz, J = 6.84 Hz, 3H, 10-H), 2.75-2.92 (m, 2H), 3.46-4.10 (m, 7H), 4.42 (dc, J = 1.70 Hz, J = 6.57 Hz, 1H), 5.96 (dc, J = 1.70 Hz, 6.21 Hz, 1H)
MS (GC / MS): m / z 157 (M ⁺ )
(iii) The crude 2- (1-propenyloxymethyl) morpholine (32.7 g) was dissolved in an acetone-aqueous (9: 1) mixed solvent containing 2.0 N HCl, followed by heating under reflux for 4 hours. After completion of the reaction, the solvent was evaporated, yielding a crude alcohol compound (41.8 g) as a pale yellow oily substance. Triethylamine (300 ml) was added dropwise to a solution of methylene chloride (300 ml) of the crude alcohol compound (41.8 g) under ice cooling, and triphenylchloromethane (41.5 g, 0.208 mol) was added at the same temperature, followed by stirring for 2 hours. After completion of the reaction, a saturated aqueous solution of sodium hydrogencarbonate (150 ml) was added to the reaction mixture, and the mixture was extracted with chloroform. The extract was dried over magnesium sulfate, the solvent was evaporated, and the residue was recrystallized from methylene chloride-hexane to give 2-hydroxymethyl-4-tritylmorpholine (48.0 g).

Physiochemical properties:
IR (KBr): 3450 cm ^-1
1 H-NMR (CDCl ₃ ) δ:
1.12-1.90 (m, 2H), 2.80-2.98 (m, 2H), 3.28-3.56 (m, 3H), 3.80-4.05 (m, 3H ), 7.06-7.58 (m, 15H, C (C ₆ H ₃ ) ₃ )
MS (FAB / pos.): M / z 350 [(M + 1) ⁺ ]
(iv) Pyridine (20.3 ml, 0.251 mol) was added dropwise to a solution in methylene chloride (100 ml) containing a trityl derivative (15.0 g) while cooling on ice, and a solution of methylene chloride (100) was added dropwise to it. ml) p-toluenesulfonyl chloride (15.9 g) at the same temperature, followed by stirring for 13 hours. After completion of the reaction, an aqueous solution of sodium hydrogencarbonate is added while cooling on ice, followed by extraction with chloroform. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was evaporated and the residue was recrystallized from 1,2-dichloroethane to give 2-p-toluenesulfonylmethyl-4-tritylmorpholine (14.0 g).

Physiochemical properties:
IR (KBr): 1730 cm ^-1
1 H-NMR (CDCl ₃ ) δ:
1.34-1.70 (m, 2H), 2.43 (s, 3H, PhCH ₃ ), 2.75-2.94 (m, 2H), 3.72-4.04 (m, 5H) 7.10-7.40 (m, 17H); 7.70 (d, J = 2.10 Hz, 2H)
MS (FAB / pos.): M / z 514 [(M + 1) ⁺ ]
Reference example 2.

(i) Phenol (8.00 g) is added to a mixed solution of an aqueous solution (50 ml) of sodium hydroxide (3.43 g) and methylene chloride (60 ml) at room temperature. Then tetrabutylammonium hydrogen sulfate (0.48 g) and acryl chloride (7.75 g) were added dropwise at 0 ^° C., followed by stirring at room temperature for 20 minutes. After completion of the reaction, the organic layer is washed successively with water and a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was removed by evaporation to give 4-fluorophenyl acrylate (13.5 g), which was used in the next step without purification.

Physiochemical properties:
¹ H-NMR (CDCl ₃ ) δ:
5.99 (dd, J = 2.43 and 9.81 Hz, 1H), 6.28 (dd, J = 9.81 and 16.7 Hz, 1H), 6.62 (dd, J = 2, 43 and 16.7 Hz, 1H), 7.08 (d, J = 5.94 Hz, 4H)
MS (GC / MS): m / z 166 (M ⁺ )
(ii) 4-fluorophenylacrylate (12.0 g) is added to a mixture of aluminum chloride (33.7 g) and sodium chloride (14.8 g), and the mixture is stirred at 80 ^° C. for 2 hours and then at 160 ^° C. within 1 hour. After completion of the reaction, ice water and concentrated hydrochloric acid were added, and the reaction mixture was extracted with chloroform. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography. From the eluate obtained using a mixture of hexane-ethyl acetate (9: 1), 4-fluoro-7-hydroxy-1-indanone (5.75 g) is obtained in the form of a pale yellow powder.

Physiochemical properties:
¹ H-NMR (CDCl ₃ ) δ:
2.68-2.82 (m, 2H), 3.08-3.20 (m, 2H), 6.73 (dd, J = 3.06 and 8.91 Hz, 1H), 7.13 ( d, J = 8.91 Hz, 1H), 8.79 (s, 1H)
MS (GC / MS): m / z 166 (M ⁺ )
(iii) 4-fluoro-7-hydroxy-1-indanone (1.0 g) was dissolved in acetic acid (15 ml), and the solution was stirred with 10% palladium-on-carbon (0.5 g) in a hydrogen atmosphere atmospheric pressure for 12 hours. The used catalyst was removed by filtration with celite, and the filtrate was concentrated to obtain 7-fluoro-4-indane (0.783 g).

Physiochemical properties:
¹ H-NMR (CDCl ₃ ) δ:
1.95-2.32 (m, 2H), 2.75-3.10 (m, 4H), 4.55 (br s, 1H), 6.54 (dd, J = 4.05 and 8 , 46 Hz, 1H), 8.46 (t, J = 8.46 Hz, 1H)
MS (GC / MS): m / z 152 (M ⁺ )
Example 1

(i) 7-fluoro-4-indanol (0.30 g) was dissolved in an aqueous solution (5 ml) of potassium hydroxide (0.157 g), and the solution was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was evaporated. To a solution of the obtained residue in dimethylformamide (20 ml) was added 2-p-toluenesulfonyloxymethyl-4-tritylmorpholine (1.69 g), followed by stirring at 105 ^° C. for 12 hours. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added while cooling on ice, and the reaction mixture was extracted with chloroform. The extract was washed with a saturated aqueous solution of sodium chloride (100 ml) and dried over magnesium sulfate. The solvent was removed by evaporation, and the residue was purified by silica gel column chromatography. After elution with a mixture of hexane-ethyl acetate (9: 1), 2 - [[(7-fluoro-4-indanyl) oxy] methyl] -4-tritylmorpholine (0.54 g) was obtained.

Physiochemical properties:
¹ H-NMR (CDCl ₃ ) δ:
1.40-2.25 (m, 2H), 2.60-3.20 (m, 6H), 3.75-4.05 (m, 5H), 6.50-7.65 (m, 17H )
MS (FAB / pos.): M / z 494 (M ⁺ +1)
(ii) To 20 ml of a solution in methanol 0.54 g of 2 - [[(7-fluoro-4-indanyl) oxy] methyl] -4-tritylmorpholine add a solution in methanol (5 ml) of concentrated hydrochloric acid (1.30 g , 12.8 mmol) at room temperature, followed by stirring for 30 minutes. After completion of the reaction, the reaction mixture was neutralized with a saturated solution of sodium hydrogencarbonate. The solvent was evaporated, and a saturated aqueous solution of sodium chloride was added to the resulting residue, followed by extraction with chloroform. The extract was washed with saturated aqueous sodium chloride and dried over sodium sulfate. The solvent was evaporated, and the obtained residue was purified by silica gel column chromatography to obtain 2 - [[(7-fluoro-4-indanyl) oxy] methyl] morpholine (0.236 g) as a colorless oily substance from the eluate obtained using a mixture of chloroform- methanol-concentrated ammonia (10: 1: 0.1).

Physiochemical properties:
¹ H-NMR (CDCl ₃ ) δ:
1.90-2.28 (m, 2H), 2.55-3.17 (m, 8H), 3.50-4.04 (m, 5H), 6.56 (dd, J = 4.23 and 8.55 Hz, 1H); 6.76 (t, J = 8.55 Hz, 1H)
MS (GC / MS): m / z 251 (M ⁺ )
The resulting 2 - [[(7-fluoro-4-indanyl) oxy] methyl] morpholine is converted into hydrochloride, which is recrystallized from methanol-diethyl ether-isopropyl ether to give white crystals.

Physiochemical properties:
mp: 169-171 ^o C
¹ H-NMR (CDCl ₃ δ:
2.06 (q, J = 7.6 Hz, 2H), 2.78-3.02 (m, 5H), 3.15-3.36 (m, 3H), 3.81 (dt, J = 2.0 Hz and 10 Hz, 1H), 3.90-4.25 (m, 4H), 6.76 (dd, J = 3.60 and 8.80 Hz, 1H), 6.90 (t , J = 8.80 Hz, 1H)
MS (GC / MS): m / z 251 (M ⁺ )
Elemental analysis for C ₁₄ H ₁₈ NO ₂ F • HCl • 0.2H ₂ O:
Calculated (%): C 57.71, H 6.71, N 4.81, Cl 12.17, F 6.52.

 Found (%): C 57.77, H 6.67, N 4.71, Cl 12.44, F 6.50.

 Example 2

 (i) In the same manner as in Example 1 - (i), except that 7-chloro-4-indanol (0.300 g) was taken, 2 - [[(7-chloro-4-indanyl) was obtained hydroxy) methyl] -4-tritylmorpholine (0.790 g) as a pale yellow powder.

Physico-chemical properties of 2 - [[(7-chloro-4-indanyl) oxy] methyl] - 4-tritylmorpholine:
¹ H-NMR (CDCl ₃ ) δ:
1.25-2.23 (m, 6H), 2.66-3.18 (m, 4H), 3.72-4.31 (m, 5H), 6.55 (d, J = 9.00 Hz, 1H), 7.04 (d, J = 9.00 Hz, 1H), 7.12-7.65 (m, 15H)
MS (FAB / pos.): M / z 522 [(M + 1) ⁺ ]
(ii) In the same manner as in Example I- (II), except that 2 - [[(7-chloro-4-indanyl) hydroxy] methyl] morpholine (0.55 g) was taken, hydrochloride 1 - [[7-chloro-4-indanyl) oxy] methyl] morpholine as a pale yellow oily substance.

Physiochemical properties:
¹ H-NMR (CDCl ₃ ) δ:
1.95-2.28 (m, 4H), 2.85-3.10 (m, 6H), 3.50-4.15 (m, 5H), 6.59 (d, J = 8.64 Hz, 1H), 7.06 (d, J = 8.64 Hz, 1H)
MS (E1): m / z 267 (M ⁺ ), 269 [(M + 2) ⁺ ]
Example 3

 An aqueous solution of potassium hydroxide (potassium hydroxide: 72.3; water: 150 ml) was added to 72.3 g of 7-fluoro-4-indanol, followed by stirring until indanol was dissolved. To this solution was added 40.8 ml of (R) - (-) - epichlorohydrin, followed by stirring for 8 hours. 1 L of water was added to the reaction mixture, and the mixture was extracted with three portions of 1 L of ethyl ether. Ethyl ether was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 97 g of an oily substance.

An aqueous solution of potassium hydroxide (potassium hydroxide: 313.5 g; water: 188 ml) was added to 670.4 g of aminoethylsulfuric acid, and then the oily substance obtained above dissolved in 600 ml of methanol was added to the solution. The mixture was stirred at 50 ^° C. for 4 hours and an aqueous solution of potassium hydroxide (potassium hydroxide: 627 g; water: 380 ml) was added, followed by further stirring at 50 ^° C. for 18 hours. To the reaction mixture was added 2 L of water, 2 L of ethyl ether. All insoluble material was removed by filtration, and the filtrate was extracted three times with 2 L of ethyl ether each time. The ethyl ether solution was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 114 g of an oily substance.

 D-dibenzoyl tartaric acid was dissolved in a mixed solvent consisting of 1 L of acetonitrile and 1.3 L of water, and the oily substance obtained above, dissolved in 0.5 L of acetonitrile, was added under reflux. After refluxing for 1 hour, the reaction mixture was cooled with stirring in an ice bath. The precipitated salt was collected by filtration, washed with acetonitrile and dried, yielding 140 g of (-) - 2 - [[(7-fluoro-4-indanyl) oxy] methyl] morpholine D-dibenzoyltartrate with an optical purity of 99.9 %.e.

Physiochemical properties:
¹ H-NMR (DMSO) δ: 2.09 (tt, J = 7.2 Hz, 2H), 2.76 (t, J = 7.6 Hz, 2H), 2.81-2.94 (m , 6H), 3.09 (d, J = 12.4 Hz, 1H), 3.21 (d, J = 12.4 Hz, 1H), 3.64-3.69 (m, 1H), 3 , 84-3.95 (m, 4H), 5.65 (s, 2H), 6.69 (dd, J = 3.6 Hz, J = 8.8 Hz, 1H), 6.89 (dd, J = 8.8 Hz, 1H), 7.51 (dd, J = 7.2 Hz, 4H), 7.64 (dd, J = 8 Hz, 2H), 7.97 (d, J = 7, 6 Hz, 4H)
MS (FAB / pos.): M / z 252 (M + 1) ⁺
Example 4

 To 10 g of (-) - 2 - [[(7-fluoro-4-indanyl) hydroxy] methyl] morpholine D-dibenzoyltartrate was added an aqueous solution of sodium hydroxide (sodium hydroxide: 4 g; water: 200 ml), and the mixture was extracted with three in 200 ml portions of methylene chloride. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. 1.91 g of fumaric acid and 110 ml of 2-propanol are added to the residue, and the mixture is heated until complete dissolution. The solution was cooled in an ice bath and the precipitated salt was collected by filtration, washed with 2-propanol and dried, yielding 5.04 g of fumarate (-) - 2 - [[7-fluoro-4-indanyl) oxy] methyl] morpholine with optical purity 99.9 %.e.

Physiochemical properties:
mp: 141-142 ^o C
Elemental analysis for C ₁₈ H ₂₂ NO ₆ F:
Calculated (%): C 58.85, H 6.04, N 3.81, F 5.17.

 Found (%): C 58.85, H 6.07, N 3.84, F 5.23.

¹ H-NMR (DMSO) δ: 2.05 (tt, J = 7.6 Hz, 2H), 2.75-2.89 (m, 8H), 3.00 (d, J = 12.4 Hz , 1H), 3.16 (d, J = 12.4 Hz, 1H), 3.63-3.69 (m, 1H), 3.88-4.01 (m, 4H), 6.51 ( s, 2H), 6.76 (dd, J = 3.6 Hz, J = 8.8 Hz, 1H), 6.89 (dd, J = 8.8 Hz, 1H)
MS (GC / MS): m / z 251 (M) ⁺ .

 Example 5

 To 107 g of (-) - 2 - [[(7-fluoro-4-indanyl) oxy] methyl] morpholine D-dibenzoyltartrate was added an aqueous solution of sodium hydroxide (sodium hydroxide: 21 g; water: 1 l), and the mixture was extracted three times in portions of 500 ml of ethyl ether. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and dissolved in 1.2 L of ethyl ether. To the solution was added 53 ml of a mixture of 4N hydrochloric acid-ethyl acetate. The precipitated salt was collected by filtration, washed with ethyl ether and dried under reduced pressure to obtain 47.8 g of (-) - 2 - [[(7-fluoro-4-indanyl) oxy] methyl] morpholine hydrochloride.

Physico-chemical properties of (-) - 2 - [[(7-fluoro-2-indanyl) oxy] methyl] morpholine hydrochloride:
so pl. 170-171 ^o C
IR (KBr): 1284 cm ^-1 , 1492 cm ^-1
1 H-NMR (DMSO) δ:
2.05 (tt, J = 7.6 Hz, 2H), 2.80-3.00 (m, 8H), 3.19 (d, J = 12.4 Hz, 1H), 3.33 (d , J = 12.4 Hz, 1H), 3.87 (t, J = 10.4 Hz, 1H), 3.98-4.04 (m, 3H), 4.13-4.15 (m, 1H), 6.77 (dd, J = 3.6 Hz, J = 8.8 Hz, 1H), 6.90 (dd, J = 8.8 Hz, 1H)
MS (GC / MS): m / z 251 (M ⁺ )
Elemental analysis for C ₁₄ H ₁₉ NO ₂ FCl • 0.05H ₂ O:
Calculated (%): C 58.25, H 6.67, N 4.85, Cl 12.28, F 6.58.

 Determined (%): C 58.14, H 6.72, N 4.84, Cl 12.18, F 6.36.

[d] $\genfrac{}{}{0ex}{}{\text{20}}{\text{D}}$ = -3.00
The compound of example 6 is obtained by the method described in example 1.

 Example 6

Fumarate 2 - [[(6-fluoro-4-indanyl) oxy] methyl] morpholine
Starting compound: 6-fluoro-4-indanol.

Physiochemical properties:
so pl. 173-174 ^o C
Elemental analysis for C ₁₈ H ₂₂ NO ₆ F:
Calculated (%): C 58.85, H 6.04, N 3.81, F 5.17.

 Determined (%): C 58.70, H 5.99, N 3.77, F 5.06.

MS (GC / MS): m / z 251 (M ⁺ )
¹ H-NMR (DMSO) δ:
2.01 (2H, tt, J = 7.32 Hz), 2.68-2.73 (3H, m), 2.77-2.86 (3H, m), 2.93 (1H, d, J = 12.21 Hz), 3.09 (1H, d, J = 11.72 Hz), 3.61 (1H, dt, J = 2.44, 11.72 Hz), 3.85-3, 88 (2H, m), 3.95-4.03 (2H, m), 6.52 (2H, s), 6.64 (2H, d, J = 10.7 Hz)
In the same manner as described in example 2, receive the compounds of examples 7 and 8.

 Example 7

Hydrobromide 2 - [[(7-fluoro-1-methyl-4-indanyl) oxy] methyl] morpholine
Physiochemical properties:
MS (m / Z): 265 (M ⁺ )
IR (KBr) cm ^-1 ; 1496, 1246
¹ H-NMR (DMSO) δ:
1.23 (d, J = 6.8 Hz, 3H), 1.62-1.70 (m, 1H), 2.22-2.31 (m, 1H), 2.70-2.78 ( m, 1H), 2.83-3.05 (m, 3H), 3.24 (d, J = 12.4 Hz, 1H), 3.33-3.41 (m, 2H), 3.73 -3.78 (m, 1H), 4.01-4.03 (m, 4H), 6.77 (DD, J = 3.6 Hz, J = 8.8 Hz, 1H), 6.90 ( dd, J = 8.8 Hz, 1H)
Example 8
Fumarate 2 - [[(7-fluoro-2-methyl-4-indanyl) oxy] methyl] morpholine
Physiochemical properties:
mp: 146-148 ^o C
MS (m / Z): 265 (M ⁺ -C ₄ H ₄ O ₄ )
¹ H-NMR (DMSO) δ:
1.18 (3H, d, 7.33 Hz), 1.64-1.71 (1H, m), 2.20-2.29 (1H, m), 2.60-2.83 (4H, m), 2.89-2.97 (1H, m), 3.00 (1H, d, 12.2 Hz), 3.05-3.70 (5H, m), 3.76-3.83 (2H, m), 3.88-3.97 (2H, m), 6.51 (2H, s), 6.73-6.76 (1H, m), 6.87-6.91 (1H , m)
Example 9

 (i) In the same manner as in Example 1- (i), except that 4-fluoro-7-hydroxy-1-indanone and 2-p-toluenesulfonyloxymethyl-4-tritylmorpholine are taken, 2 - [[4- (7-fluoro-3-hydroxyindanyl) oxy] methyl] -4-tritylmorpholine.

¹ H-NMR (CDCl ₃ ) δ: 1.40-1.70 (2H, m), 2.62-2.80 (2H, m), 3.03-3.25 (2H, m), 3 , 28-3.53 (1H, m), 3.55-3.72 (1H, m), 3.84-4.22 (4H, m), 4.31-4.57 (1H, m) 6.68-6.78 (1H, m), 7.10-7.60 (16H, m)
MS (m / z): 507 (M ⁺ )
(ii) 2 - [[4- (7-fluoro-3-oxoindanyl) oxy] methyl] -4-tritylmorpholine (507 mg, 1.00 mmol) was dissolved in methanol (30 ml) and sodium borohydride (37.8 mg, 1.00 mmol), followed by stirring at room temperature for 1 hour. After completion of the reaction, the precipitated colorless crystals were collected by filtration to obtain 2 - [[(7-fluoro-3-hydroxy-4-indanyl) oxy] methyl] -4-tritylmorpholine (220 mg). Water was added to the filtrate, the mixture was extracted with chloroform, the extract was dried over anhydrous sodium sulfate, and the solvent was removed by evaporation under reduced pressure to obtain 2 - [[4- (7-fluoro-3-hydroxy-4-indanyl) oxy] methyl] -4 tritylmorpholine (282 mg) as colorless crystals. The resulting crystals were combined with previously collected crystals to give 2 - [[4- (7-fluoro-3-hydroxy-4-indanyl) oxy] methyl] -4-tritylmorpholine (502 mg, 0.986 mmol, 99%). The product was dissolved in ethanol (100 ml), and concentrated hydrochloric acid (300 ml) was added to the solution, followed by heating under reflux for 1 hour. The reaction mixture was made slightly alkaline by adding a saturated aqueous solution of sodium hydrogen carbonate, ethanol was removed by evaporation under reduced pressure, and the residue was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, and the residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to obtain 2 - [[4- (3-ethoxy-7-fluoro-4-indanyl) oxy] methyl] - morpholine (257 mg, 93%) as a colorless oily substance.

MS (m / z): 295 (M ⁺ )
¹ H-NMR (CDCl ₃ ) δ:
2.20 (3H, t, J = 7.1 Hz), 1.88 (1H, br s), 2.13-2.27 (2H, m), 2.50-3.25 (6H, m), 3.35-4.20 (5H, m), 3.60 (2H, q, J = 7.1 Hz), 4.49-5.15 (1H, m), 6.62 (1H dd, J = 8.4, 3.8 Hz), 6.83 (1H, dd, J = 8.4, 8.4 Hz)
(iii) 2 - [[4- (3-ethoxy-7-fluoro-4-indanyl) oxy] methyl] morpholine (230 mg, 0.824 mmol) was dissolved in 1,4-dioxane (150 ml) and added to the solution p-toluenesulfonic acid (231 mg, 1.65 mmol), followed by heating at 105 ^° C. for 4 hours with stirring. The reaction is carried out without a condenser with a reactor to evaporate the resulting ethanol, and the loss of solvent (1,4-dioxane) during evaporation is slowly made up in order to maintain a constant concentration. After completion of the reaction, sodium hydrogen carbonate was added to the reaction mixture, and the solvent was removed by evaporation under reduced pressure. The residue was dissolved in chloroform, washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was dried chromatographically on a silica gel column (chloroform: methanol = 10: 1) to obtain 2 - [[(7-fluoro-4-indenyl) oxy] methyl] morpholine (134 mg, 0.526 mmol, 65%) as a pale yellow oily substance. This product was dissolved in ethyl ether-methanol in a mixed solvent, and a methanol solution of fumaric acid (30 mg, 0.259 mmol) was slowly added dropwise to the solution with stirring, followed by further stirring for 30 minutes. Precipitated colorless crystals were collected by filtration to obtain a mixture of 1 - [[(7-fluoro-4-indenyl) oxy] methyl] -morpholine (1/2) fumarate and 2 - [[(4-fluoro-7-indenyl) oxy] fumarate] methyl] morpholine (1/2) (115 mg, 45% based on 2 - [[4- (3-ethoxy-7-fluoro-4-indanyl) oxy] methyl] morpholine). The positional olefin isomer ratio is approximately 1: 1 based on ¹ H-NMR.

MS (m / s): 249 (M ⁺ - 1/2 C ₄ H ₄ O ₄ )
¹ H-NMR (DMSO-d ₆ ) δ:
2.68-1.81 (2H, m), 2.90 (1H, d, 12.2 Hz), 1.10 (1H, d, 12.2 Hz), 3.38-3.41 (1H , m), 3.45-3.49 (1H, m), 3.58-3.64 (1H, m), 3.85-3.88 (2H, m), 3.99-4.08 (2H, m), 6.50 (1H, s), 6.59-6.66 (1H, m), 6.82-7.06 (3H, m)
Elementary analysis for C ₁₆ H ₁₈ NO ₄ F • 0.4 H ₂ O:
Calculated (%): C 61.13, H 5.77, N 4.31, F 5.79.

 Determined (%): C 61.10, H 6.02, N 4.45, F 6.04.

 Example 10

320 mg (0.68 mmol) of 2 - [[(7-fluoro-3-oxo-4-indanyl) oxy] methyl] -4-tritylmorpholine are dissolved in 10 ml of dry THF, a solution of 1.16 diethyl ether is added to the solution M methyl lithium (3.27 ml, 3.78 mmol) in an alcohol atmosphere at -78 ^° C, followed by stirring for 2 hours. After completion of the reaction, the temperature was raised to room temperature and a saturated aqueous solution of ammonium chloride was added. The mixture was extracted with chloroform, the extract was dried over anhydrous sodium sulfate, and the solvent was removed by evaporation under reduced pressure. The residue was dissolved in a mixed solvent of ethyl acetate (5 ml) and acetic acid (5 ml), and palladium-on-carbon (500 mg) was added to the solution. The solution was stirred at room temperature for 12 hours under a hydrogen atmosphere.

 After completion of the reaction, insoluble material was removed by filtration, and the solvent was removed from the filtrate by evaporation under reduced pressure. A 1 N aqueous sodium hydroxide solution was added to the residue, and the solution was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol: aqueous ammonia = 20: 1: 0.1) to obtain 2 - [[(7-fluoro-3-methyl-4-indanyl) oxy] methyl] morpholine (73 mg 0.28 mmol, 44%) as a pale brown oily substance. This product was dissolved in ethyl ether-methanol in a mixed solvent, and a methanol solution of fumaric acid (15 mg, 0.129 mmol) was slowly added to the solution with stirring. The precipitate was collected by filtration to obtain 2 - [[(7-fluoro-3-methyl-4-indanyl) oxy] methyl] morpholine fumarate (66 mg, 33% based on 2 - [[(7-fluoro-3-oxo- 4-indanyl) hydroxy] methyl] -4-tritylmorpholine) as colorless crystals.

mp: 133 - 134 ^o C, 143 - 144 ^o C
MS (m / z): 265 (M ⁺ -1 / 2C ₄ H ₄ O ₄ )
¹ H-NMR (DMSO-d ₆ ) δ:
1.19 (3H, d, 7.33 Hz), 1.64 - 1.72 (1H, m), 2.19 - 2.29 (1H, m), 2.62 - 3.04 (6H, m), 3.30 (1H, br s), 3.53 - 3.59 (1H, m), 3.73 - 3.88 (2H, m), 3.88 - 4.00 (2H, m), 6.49 (1H, s), 6.73 - 6.76 (1H, m), 6.89 - 6.91 (1H, m)
Elemental analysis for C ₁₇ H ₂₂ NO ₄ F:
Calculated (%): C 62.99, H 6.78, N 4.26, F 5.63.

 Determined (%): C 63.14, H 6.86, N 4.33, F 5.88.

 Example 11

To 180 mg of 2 - [[(7-fluoro-4-indanyl) oxy] methyl] morpholine, 1 ml of a 35% aqueous formaldehyde solution and 1 ml of formic acid were added and the mixture was stirred at 80 ^° C. for 7 hours, followed by concentration under reduced pressure. The concentrate is neutralized by adding 20 ml of a saturated aqueous solution of sodium hydrogencarbonate. The mixture is extracted three times with 20 ml of ethyl ether each time. The ethyl ether solution was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting oil was dissolved in 20 ml of ethyl ether, and a solution of 42 mg of fumaric acid in 1 ml of methanol was added to the solution with stirring. The precipitated salt was collected by filtration, washed with ethyl ether and dried, yielding 123 mg of 4-methyl-2 - [[(7-fluoro-4-indanyl) oxy] methyl] morpholine fumarate.

so pl. 157 - 159 ^o C
Elemental analysis for C ₁₉ H ₂₄ NO ₆ F:
Calculated (%): C 59.63, H 6.34, F 3.67.

 Determined (%): C 59.63, H 6.31, F 3.69.

 Example 12

 220 mg of 2 - [[(7-fluoro-4-indanyl) oxy] methyl] morpholine is dissolved in 3 ml of acetone, and 121 mg of potassium carbonate and 70 μl of ethyl iodide are added to the solution, followed by reaction under reflux for 3 hours. 20 ml of water are added to the reaction mixture, and the mixture is extracted with three portions of 20 ml of chloroform. The chloroform solution was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting oil was dissolved in 20 ml of ethyl ether, and 260 μl of a solution of 4N hydrochloric acid in ethyl acetate was added to the solution with stirring. The precipitated salt was collected by filtration, washed with ethyl ether and dried, yielding 214 mg of 4-ethyl-2 - [[(7-fluoro-4-indanyl) oxy] methyl] morpholine hydrochloride.

mp: 199 - 201 ^o C
Elemental analysis for C ₁₆ H ₂₃ NO ₂ FCl:
Calculated (%): C 60.85, H 7.34, N 4.44, Cl 11.23, F 6.02.

 Determined (%): C 60.44, H 7.38, N 4.38, Cl 11.22, F 5.86.

(Examples of finished forms)
Examples of formulations for the compounds of the present invention for use as pharmaceuticals are described below.

An example of an oral preparation of the compound of Example 5:
Composition - Tablet 20 mg
The compound of example 5 to 20
Lactose - 73.1
Corn Starch - 18.8
Hydroxypropyl cellulose - 4
Calcium Carboxymethyl Cellulose - 4
Magnesium Stearate - 0.8
Total - 120 mg
Each tablet contained 20 mg of the compound of Example 5:
The compound of Example 5 (100 g), lactose (385.5 g) and corn starch (91.5 g) were uniformly mixed using a granulation device using a fluidized bed for coating (manufactured by Ohkawara Seisakusho) and a 10% aqueous solution of hydroxypropyl cellulose (200 g) applied to the crushed material for granulation. After drying, the granules are passed through a 20 mesh sieve, combined with calcium carboxymethyl cellulose (20 g) and magnesium stearate (3 g) and tabletted with a rotauion tablet machine (manufactured by Hata Tekkosho) using a die (7 mm • 8.4R) to give tablets with a mass of 120 mg (each).

Claims (7)

1. A morpholine derivative of the general formula I

where R ¹ and R ³ , the same or different, each represent a hydrogen atom or a lower alkyl group;
R ² is halogen;
the dotted line indicates an optional double bond,
or a pharmaceutically acceptable salt thereof.  2. The derivative according to claim 1 or its pharmaceutically acceptable salt, characterized in that the morpholine derivative is a levorotatory optical isomer.  3. The derivative of claim 1, wherein the morpholine derivative is 2 - {[(7-fluoro-4-indanyl) oxy] methyl] morpholine.  4. The derivative of claim 2, wherein the morpholine derivative is (-) - 2 - {[(7-fluoro-4-indanyl) oxy] methyl} morpholine.  5. The derivative according to claim 1, characterized in that the morpholine derivative is fumarate (-) - 2 - {[(7-fluoro-4-indanyl) hydroxy] methyl} morpholine.  6. The derivative according to claim 1, characterized in that the morpholine derivative is (-) - 2 - {[(7-fluoro-4-indanyl) hydroxy] methyl} morpholine hydrochloride. 7. A pharmaceutical composition having antagonism of 5-HT ₂ receptors and inhibiting 5-HT reassimilation activity, comprising a morpholine derivative and a pharmaceutically acceptable carrier as an active ingredient, characterized in that it contains a compound according to any one of paragraphs as a morpholine derivative. 1-6 or a pharmaceutically acceptable salt thereof. Priority by signs and points:
02/10/93 when R ¹ is hydrogen, R ² is halogen, R ³ is hydrogen, there is no dashed line, or salts of the corresponding compounds;
02/08/94 at R ¹ and R ² , the same or different, each represents a hydrogen atom or a lower alkyl group, a dotted line may indicate the optional presence of a double bond, provided that the compounds where both R ¹ and R ³ represent hydrogen atoms are excluded , or salts of the corresponding compounds, and according to claim 7.

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