WO2001017993A1

WO2001017993A1 - Alkylpiperidi nylbenzo [d] isoxazole derivatives having psychotropic activity, pharmaceutical compositions containing the same, and a process for the preparation of the active ingredient

Info

Publication number: WO2001017993A1
Application number: PCT/HU2000/000096
Authority: WO
Inventors: József Barkóczy; István Gacsályi; László BALÁZS; György Lévay; Gyula Simig; Éva SCHMIDT; Katalin Pallagi; Gábor SZÉNÁSI; Imre Domán; Zoltán Greff; Péter KÓTAY-NAGY; Zoltán RÁTKAI; Péter SERES
Original assignee: Egyt Gyogyszervegyeszeti Gyar; Egis Pharmaceuticals PLC
Current assignee: Egyt Gyogyszervegyeszeti Gyar; Egis Pharmaceuticals PLC
Priority date: 1999-09-09
Filing date: 2000-09-07
Publication date: 2001-03-15
Anticipated expiration: 2002-03-09
Also published as: AU7547100A

Abstract

The invention refers to novel alkylpiperidinylbenzo[d]isoxazole derivatives of formula (I), pharmaceutical compositions containing the same, and a process for the preparation of the active ingredient. The compounds of the invention exert action on the central nervous system, and have, primarily, psychotropic activity.

Description

ALKYLPIPERIDI NYLBENZO [D] ISOXAZOLE DERIVATIVES HAVING PSYCHOTROPIC ACTIVITY, PHARMACEUTICAL COMPOSITIONS COOTAJLNING THE SAME, AND A PROCESS FOR THE PREPARAΗON OF THE ACTIVE INGREDIENT

The invention refers to novel alkylpιpeπdιnylbenzo[d]ιsoxazole derivatives, pharmaceutical compositions containing the same, and a process for the preparation of the active ingredient The compounds of the invention exert action on the central nervous system and have primarily, psychotropic activity

Especially, the invention refers to novel alkylpipeπdinylbenzo- [d]ιsoxazole derivatives of the formula

wherein

Z represents a hydrogen atom or a hydroxy group, n has a value of 0 or 1 , and a)

X and Y mean, independently, a hydrogen atom, and simultaneously R stands for a hydrogen atom a halo atom a C_1-6 alkyl group or a Cι_-6 alkoxy group, and

X' and Y' represent, independently, a hydrogen atom, a halo atom, a d_-6 alkyl group or a C_1-6 alkoxy group, or

X' forms together with Y' a 5- to 7-membered aromatic or partially saturated isocyclic or heterocyclic ring that can be fused with one or more further 5- to 7-membered aromatic or partially saturated isocyclic or heterocyclic ring, wherein each heterocyclic ring may contain, independently, one or more oxygen atom(s) and/or nitrogen atom(s) and/or sulfur atom(s) as the heteroatom and each isocyclic or heterocyclic ring may be independently substituted by a halo atom, a Cι-₆ alkyl group and/or a C_1-6 alkoxy group, or b)

R, X' and Y' represent, independently, a hydrogen atom and

X forms together with Y a 5- to 7-membered aromatic or partially saturated isocyclic or heterocyclic ring that can be fused with one or more further 5- to 7-membered aromatic, partially saturated or saturated isocyclic or heterocyclic ring, wherein each heterocyclic ring may contain, independently, one or more oxygen atom(s) and/or nitrogen atom(s) and/or sulfur atom(s) as the heteroatom, and each isocyclic or heterocyclic ring may be independently substituted by a Cι-₆ alkyl group or a Cι_-6 alkoxy group, and pharmaceutically suitable acid addition salts thereof

The psychiatric disorders including the affective clinical patterns (schizophrenia anxiety, depression) form a great challenge for the medical science As to schizophrenia, about 1 % of the entire population is involved However, the medicinal therapy currently used is not thoroughly appropriate for the treatment of the disease Up to now, the so called conventional neuroleptics (such as haloperidol i e 4-/4-(4-chlorophenyl)-4- hydroxy-1 -pipeπdinyl -(4-fluorophenyl)-1 -butanone, chlor- promazine i e 2-chloro-N,N-dιmethyl-10H-phenothιazιπe-10- propanamine) dominate the therapy These neuroleptics are primarily dopamine D₂ receptor antagonists, consequently, possess several disagreeable side-effects Furthermore they are ineffective in certain symptom complex of schizophrenia (negative symptoms) [Ellenbroek, B A , Pharmacol Ther , 57, 1 (1993)]

After the discovery of 5-HT_2A receptors [Leysen et al , Biochem Pharmacol , 27, 307 ( 978)], the role of said receptors became upgraded in the therapeutical effect of antischizophrenia drugs The clozapine [8-chloro-11 -(4-methyl-1 -pιperazιnyl)-5H- dιbenzo[b,e][1 ,4]dιazepιne] was the first agent having stronger affinity to the 5-HT_2A receptors than to the D₂ receptors and did not possess the unfavourable side-effects that characterized the conventional drugs [Melzer, H Y , Schizophr Bull 1_7, 263 (1991)] Clozapine was followed by numerous neuroleptics of new generation such as olanzapme [2-methyl-10-(4-methyl-1 - pιperazιnyl)-4H-thιeno[2,3-b][1 ,5]benzodιazepιne], quetiapine [2-/2-(4-dιbenzo[b,f][1 ,4]thιazepιn-11 -yl-1 -pιperazιnyl)ethoxy/- ethanol] etc , however, up to this time, clozapine can be considered as the standard atypic neuroleptic It was found that the novel alkylpιperιdιnylbenzo[d]ιsoxazole derivatives of the formula I are characterized by valuable psychotropic activity The compounds of the invention display effects characteristic to the atypical neuroleptics, anxiolytic effect as well as psychosedative activity

In the description a C-ι_-6 alkyl group is, for example, a methyl, ethyl, n-propyi, isopropyl, n-butyl, sec -butyl, tert -butyl, isobutyl n-pentyl or n-hexyl group

A C₁-₄ alkoxy group is a methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec -butoxy, tert -butoxy or isobutoxy group

A C₁.₆ alkoxy group can be, in addition to the ones listed in the definition of the Cι- alkoxy group, e g also an n-pentyloxy or n- hexyloxy group

A halo atom is, for example, a fluoro, chloro, bromo or lodo atom

Under a 5- to 7-membered aromatic or partially saturated isocyclic or heterocyclic ring, a ring consisting of only carbon atoms or containing in addition to the carbon atoms one or more heteroatom(s) and having 5, 6 or 7 members is meant, wherein the ring is either of aromatic structure, or partially saturated lf X forms together with Y such a ring, then this ring is naturally fused with the benzene ring to which X and Y are bound The isocyclic or heterocyclic ring defined above may be fused with one or more further rιng(s) that correspond(s) to the above definition or is/are completely saturated, wherein each heterocyclic ring may contain, independently, one or more oxygen atom(s) and/or one or more (nitrogen atom(s) and/or one or more sulfur atom(s) Each isocyclic or heterocyclic ring of the ring system can be, independently substituted

If X' forms together with Y' a ring that corresponds to the above definition, then this ring is naturally fused with the benzene ring to which to which X' and Y' are bound The isocyclic or heterocyclic ring defined above may be fused with one or more further nng(s) that correspoπd(s) to the above definition wherein each heterocyclic ring may contain, independently, one or more oxygen atom(s) and/or one or more (nitrogen atom(s) Each isocyclic or heterocyclic ring of the ring system can be independently, substituted

For example, X can form together with Y (or X' can form together with Y') a furan, pyrazole, imidazole, tπazole isoxazole oxazole, oxadiazole, cyclopeπtene, benzene pyridine, pyridazine, pyrimidine, pyrazine, triazine oxazine, azepine diazepine, indene, benzofuran, indole, benzisoxazole, naphthalene ring etc

A pharmaceutically suitable acid addition salt is an acid addition salt formed with a pharmaceutically suitable inorganic acid such as hydrogen chloride hydrogen bromide, sulfuric acid, phosphoric acid etc , or with a pharmaceutically suitable organic acid such as formic acid acetic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, succinic acid, citric acid methanesulfomc acid etc

The invention includes any possible optical isomers of the alkylpιperιdιnylbenzo[d]ιsoxazole derivatives of the formula I and the mixtures thereof

A preferred subgroup of the compounds of the invention consists of the alkylpιperιdιnylbenzo[d]ιsoxazole derivatives and pharmaceutically suitable acid addition salts thereof, wherein in formula I

Z represents a hydrogen atom or a hydroxy group R, X' and Y' mean, independently, a hydrogen atom, X forms together with Y a 5- to 6-membered aromatic or partially saturated isocyclic or heterocyclic ring, said latter ring containing one or more oxygen atom(s) and/or nitrogen atom(s) and/or sulfur atom(s) as the heteroatom and the isocyclic or heterocyclic ring can be substituted by a Ci ₄ alkyl group or a Cι. alkoxy group, n has a value of 0 or 1

Within the above subgroup, the especially preferred alkyl- pιpeπdιnylbenzo[d]ιsoxazole derivatives consist of the compounds of the formula I wherein Z represents a hydrogen atom or a hydroxy group, R, X' and Y' mean, independently, a hydrogen atom, X forms together with Y a benzene ring or a 5-membered aromatic or partially saturated heterocyclic ring containing two oxygen atoms or two nitrogen atoms and a sulfur atom as the heteroatom, n has a value of 0 or 1 , and pharmaceutically suitable acid addition salts thereof.

A further preferred subgroup of the compounds of the invention consists of alkylpiperidinylbeπzo[d]isoxazole derivatives of the formula

wherein

Z represents a hydrogen atom or a hydroxy group,

R stands for a hydrogen atom,

X' and Y' mean, independently, a hydrogen atom or a Cι_-4 alkoxy group, or

X' forms together with Y' a 5- to 6-membered aromatic or partially saturated isocyclic or heterocyclic ring, said latter ring containing two oxygen atoms or a nitrogen atom as the heteroatom, and the isocyclic or heterocyclic ring is optionally fused with a benzene ring, n has a value of 0 or 1 , and pharmaceutically suitable acid addition salts thereof

Within the latter subgroup, the especially preferred alkyl- pιperιdιnylbenzo[d]ιsoxazole derivatives consist of the compounds of the formula la, wherein

Z represents a hydrogen atom or a hydroxy group

R stands for a hydrogen atom,

X' and Y' mean, independently, a hydrogen atom or a methoxy group, or X' forms together with Y a benzene ring or pyrrol ring which latter is fused with a benzene ring, n has a value of 0 or 1 , and pharmaceutically suitable acid addition salts thereof

The alkylpιperιdιnylbenzo[d]ιsoxazole derivatives of the formula

I are prepared as follows a) a pιpeπdιnylbenzo[d]ιsoxazole derivative of the formula

wherein A stands for a leaving group, Z and n are as defined in connection with formula I, is reacted with a phenol derivative of the formula

wherein X Y, X', Y' and R are as defined in connection with formula I or b) a compound of the formula

wherein Q represents a leaving group, Z' stands for a hydrogen atom or a hydroxy group or Q forms together with Z' an oxygen atom X, Y, X', Y', R and n are as defined in connection with formula I, is reacted with 6-fluoro-3-(pιpeπdιne-4-yl)benzo[d]- isoxazole, and, if desired, an obtained alkylpιperιdιπylbenzo[d]ιsoxazole derivative of the formula I is converted to a pharmaceutically suitable acid addition salt or the base is liberated from the salt

Processes a) and b) of the invention are carried out in an analogous way as the processes known from the literature [Houben-Weyl Methoden der Organischen Chemie, VI/3 54- 62, 465-468, Xl/L_. 311 , XI/2, 407, 654, 656, Georg Thieme Verlag, Stuttgart]

The pιperιdιnylbeπzo[d]ιsoxazole derivative of the formula II used as starting compound in process a) of the invention can be prepared by the reaction of a compound of the formula

wherein A and Q represent, independently, a leaving group, Z' stands for a hydrogen atom or a hydroxy group, or Z forms together with Q an oxygen atom, n is as defined in connection with formula I, with 6-fluoro-3-pιpeπdιne-4-ylbenzo[d]ιsoxazole in an analogous way as the processes known from the literature [Houben-Weyl Methoden der Organischen Chemie, XI/2 407, 654, 656, Georg Thieme Verlag, Stuttgart]

In process b) of the invention the compound of the formula III used as the starting substance is prepared by the reaction of a phenol derivative of the formula IV with the compound of the formula V in an analogous way as the processes known from the literature [Houben-Weyl Methoden der Organischen Chemie, VI/3, 54-62, Georg Thieme Verlag Stuttgart]

The pharmacological effect of the compounds of the invention was studied on the following tests 1. Antipsychotic effect

1 1 Inhibition of conditioned avoidance response (CAR)

The antipsychotic (neuroleptic) effect was evaluated by the assessment of inhibition of the learned conditioned avoidance response The experiments were done on male Wistar rats weighing 120 to 150 g (at the beginning of conditioning) The experimental apparatus (shuttle-box) consisted of two 24x24 5x23 cm compartments connected by a 6x9 cm passage way In the shuttle-box avoidance test, the animals were conditioned to avoid punishment (electric shock) by passing from one compartment to the other after a neutral signal was delivered The warning (conditioned) signal was given in the very compartment occupied by the animal in the moment of signaling Blinking white light was used as conditioned signal (CS) for 15 sec 0 6 mA randomized electric foot shock started in the last 5 sec of the CS was employed as unconditioned signal (UCS) Passage of the animal through the gate from one compartment of the apparatus to the other during CS was considered as avoidance response, while passing during UCS was determined as escape response Both responses stopped the existent signal, the trial was terminated Intertnal interval (ITI) lasted for 15 sec Daily sessions consisted of 80 trials Learning performance was expressed as percent of avoidance response in the total number of trials The effect of neuroleptics was examined in animals performing at the 75 % level or above The animals were treated with the test compounds weekly once 1 h before the experimental session Performance of the same animals in the preceding day was used as control value From the data obtained, 50 % inhibitory doses (ID₅₀) were calculated for each compound Results are shown in Table 1 Chlorpromazine and clozapine were used as reference compounds

Table 1 Inhibition of conditioned avoidance response (CAR)

Compound (Example No.) CAR inhibition, ID₅₀ in mg/kg

1 1 0

2 3 9

6 23 5

7 15 6

8 10 0

9 16 9

10 13 0

11 1 3

12 7 0

13 0 8

17 2 1

19 21 9

27 25 6 chlorpromazine 13 2 clozapine 21 3 The novel compounds examined were effective at the inhibition of conditioned avoidance response The ID₅o values of the compounds according to Examples 1 , 2, 11 , 12, 13 and 17 were lower by one order of magnitude than that of the reference compounds The compound of Example 6 displayed inhibition of CAR with an ID₅₀ value similar to that of the atypical neuroieptic clozapine

1 2 Inhibition of apomorphine induced stereotypes and climbing

Male NMRI mice weighing 20 to 25 g were used in the experiments 30 mm after oral administration (20 ml/kg) of the test compound or vehicle, the animals were placed in a 12x12x12 cm wire mesh cage covered with plexiglass top for habituation After 30 mm, mice were treated subcutaneously with 1 mg/kg of apomorphine hydrochloride in 10 ml/kg volume Stereotyped behaviour was scored from 0 to 4 for 25 mm according to the following criteria

0 = absence of stereotyped behaviour, similar to control,

1 = presence of continuous exploration, intermittent sniffing and lateral movements of head; = intense stereotyped movements of head and/or sniffing, periodic exploration, = intense sniffing or head weaving with intermittent licking, biting or gnawing, = intense licking or gnawing confined to a small area without exploration and locomotion

Climbing behaviour was scored in an "all or none" manner 15 minutes after apomorphine administration for 10 minutes The reaction was considered positive when the mouse climbed with at least 3 paws on the wire mesh wall

Evaluation of stereotypes data

The highest score was recorded for each animal Medians for each group were calculated from the maximal score values The inhibition of stereotyped behaviour was calculated as per cent of control ID₅₀ values were calculated by linear repression analysis using per cent inhibitions

Evaluation of climbing behaviour

Climbing frequency was calculated for each group The result of the control group was considered as 100 % ED₅₀ values were computed by the method of Litchfield and Wilcoxoπ [J Pharmacol Exp Ther , 96, 99 (1949)] from the dose-response data The results are summarized in Table 2 Chlorpromazine and clozapine were used as reference compounds Table 2

Inhibition of apomorphine induced stereotypes, climbing and ratio of the two parameters

Compound Inhibition of Inhibition of Ratio of

(Example No ) stereotypes, climbing, stereotypes

IDso mg/kg ED50 mg/kg and climbing p.o. p.o.

1 14 02 70

2 07 01 70

5 10 02 50

6 60 24 25

7 60 10 60

8 19 03 60

9 41 10 40

10 13 04 30

11 11 05 20

12 06 01 60

13 06 01 60

17 46 02 230

23 115 30 38

24 180 60 30

27 90 06 150 chlor68 61 11 promazine clozapine 354 118 30 The novel compounds examined significantly inhibited both stereotyped behaviour and climbing Moreover, inhibition of climbing occurred in a much lower dose than inhibition of stereotyped behaviour The efficiency of the compounds of the invention is greater than that of clozapine and chlorpromazine The compounds of Examples 17 and 27 displayed extreme selectivity to climbing over stereotyped behaviour

2. Anxiolytic effect

2 1 Vogel lick conflict

Male Wistar rats weighing 160 to 180 g were used Rats were deprived of drinking water 48 hours prior to the test and were fasted for 24 hours before the test The compounds to be tested or the vehicle were administered intraperitoneally 30 mm prior to the experiments in a volume of 5 ml/kg The experimental chamber (20x20x20 cm plexiglass box) was equipped with a water fountain mounted at the appropriate height on the wall of the chamber An electric shock (700 μA, 0 1 s) was applied through the drinking spout at every 20th lick during the 5 minutes test period The number of tolerated shocks was recorded Per cent increase in tolerated shocks was calculated Minimum effective dose (MED) was calculated for each treatment group according to Vogel et al [Psvchopharmacologia, 21 1 (1971)] The results are summarized in Table 3 Diazepam [7-chloro-1 ,3-dιhydro-1 - methyl-3-phenyl-2H-1 ,4-benzodιazepιne-2-one] was used as the reference compound

Table 3 Vogel lick conflict test

Compound (Example No.) MED in mg/kg

21 10 0

23 5 0

24 5 0

27 1 2 diazepam 5 0

The novel compounds examined displayed significant anxiolytic activity in the lick conflict model With the exception of the compound according to Example 21 , all compounds examined showed effectiveness similar to that of diazepam, while the efficacy of the compound of Example 27 was remarkably higher than that of the reference compound

2 2 Elevated plus maze in rats

The study was performed in groups of male Sprague-Dawley rats weighing 200 to 220 g according to Pelow et al [J Neurosci Methods, 14 149 (1985)] The animals were treated per os with the compounds to be examined or the vehicle 60 minutes before testing

The arms of the plus-maze were 50 cm long and 15 cm wide, the walls of the closed arms were 40 cm high The maze was elevated to 60 cm height from floor level The behaviour of the animals in the maze was observed through a video camera in an adjacent room During the 5 minutes test period, the number of entries into the open and closed arms as well as the cumulative time spent by the rat in the open and closed arms were recorded

A significant increase in time spent in the open arms and number of entries into the open arms was considered as anxiolytic effect Minimum effective dose (MED) for each compound was calculated for the time spent in the open arms The results are summarized in Table 4 Buspirone [8-[4-/4-(2- pιπmιdιnyl)-1 -pιperazιnyl/butyl]-8-azaspιro[4,5]decane-7,9- dione] was used as the reference compound

Table 4 Elevated plus-maze test in rats

Compound (Example No.) MED in mg/kg

21 1 0

24 10 0

27 3 0 buspirone 3 0 The novel compounds examined displayed anxiolytic effect on the elevated plus-maze The compound of Example 21 produced significantly stronger anxiolytic effect when compared to the reference compound buspirone

3. Inhibition of DOI-induced hyperthermia

Male Wistar rats weighing 200 to 220 g were used Core temperature was measured in the rectum of the animals using a diode probe connected to the thermometer equipped with digital display Baseline temperature was determined in each group one day before the experiment A second baseline temperature was determined again 60 mm before DOI treatment 30 mm after the second baseline measurement the animals were treated intraperitoneally with the test compound or the vehicle After 30 mm, 0 25 mg/kg of DOI was administered subcutaneously to the animals Rectal temperatures were measured 30, 60 and 90 m after DOI- jection Temperature differences (Δt) were determined for each group using the second baseline temperature measurements as starting and the 30, 60 and 90 mm measurements as endpomt values Means of Δt values were calculated for each group Data were analysed using one way ANOVA followed by Duncan's test for post hoc comparisons Minimum effective dose (MED) was determined for each compound The results obtained are summarized in Table 5

Table 5 Inhibition of DOI-induced hyperthermia

Compound (Example No.) Inhibition of hyperthermia, MED in mg/kg p.o.

1 1 0

2 3 0

5 3 0

6 3 0

9 lower than 1 0

21 10 0

23 3 0

24 1 0

27 1 0

The data of Table 5 show that the compounds of the inhibition inhibited DOI-enduced hyperthermia in a significant manner

According to the data presented above, the compounds of the invention are effective in the treatment of various mental and mood disorders It is particularly remarkable that the compounds of the invention inhibit apomorphine induced climbing in a significantly lower dose than apomorphine induced stereotyped behaviour (Table 2) These results are particularly important as inhibition of apomorphine induced stereotypes is connected to the blockade of stnatal dopaminergic receptors, while inhibition of apomorphine induced climbing is associated with the blockade of dopamine receptors of the nucleus accumbens [Costall et al , Eur J Pharmacol , 50, 39 (1978)] Thus, compounds inhibiting apomorphine induced stereotypes and climbing in about the same dosage range are most likely to produce extrapyramidal side effects in the therapeutically effective doses The so called atypical antipsychotics such as clozapine inhibit apomorhme induced climbing in a lower dose than stereotyped behaviour [Moore, N C and Gershon, S , Clin Neuropharmacol , 12, 167 (1989)] The presence of 5-HT_2A antagonist properties of the compounds of the invention is a further therapeutic advantage These attributes are established by receptor binding studies and DOI interaction models such as inhibition of DOI-induced hyperthermia [Mazzola et al Psychopharmacology, 1 17, 193 (1995)] Neuroleptic compounds with significant 5-HT_2A binding (e g clozapine, olanzapine) are not only active by reducing the positive symptoms of schizophrenia (i e hallucinations, delusions), but have an impact on the negative symptoms (emotional withdrawal, autism etc ), too [Goldstein J M , Exp Opin Invest Drugs, 4, 291 (1995)] Beside the antipsychotic characteristics, the compounds display additional anxiolytic properties Due to these effects, the compounds may be suitable as psychotropic agents for both the treatment of schizophrenia in higher doses (25 to 250 mg/die) and stress or disease related psychoneurotic disorders or anxiety in lower doses (2 to 10 mg/die)

Thus, the novel alkylpιperιdιnylbenzo[d]ιsoxazole derivatives of the formula I and pharmaceutically suitable acid addition salts thereof can be used as active ingredients in pharmaceutical compositions

The pharmaceutical compositions of the invention contain a therapeutically active amount of the compound of the formula I or a pharmaceutically suitable acid addition salt thereof and one or more conventional carrιer(s)

The pharmaceutical compositions of the invention are suitable for peroral, parenteral or rectal administration or for local treatment, and can be solid or liquid

The solid pharmaceutical compositions suitable for peroral administration may be powders capsules tablets, film-coated tablets, microcapsules etc , and can comprise binding agents such as gelatine, sorbitol, poly(vιnylpyrrolιdone) etc , filling agents such as lactose, glucose, starch calcium phosphate etc , auxiliary substances for tablettmg such as magnesium stearate, talc, poly(ethyleπe glycol), silica etc , wetting agents such as sodium laurylsulfate etc as the carrier The liquid pharmaceutical compositions suitable for peroral administration may be solutions, suspensions or emulsions and can comprise e g suspending agents such as gelatine, carboxymethylcellulose etc emulsifiers such as sorbitane monooleate etc , solvents such as water, oils, glycerol, propylene glycol ethanol etc , preservatives such as methyl p- hydroxybenzoate etc as the carrier

Pharmaceutical compositions suitable for parenteral administration consist of sterile solutions of the active ingredient, in general

Dosage forms listed above as well as other dosage forms are known per se, see e g Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Co , Easton, USA (1990)

The pharmaceutical compositions of the invention contain, in general, 0 1 to 95 0 per cent by mass of a compound of the formula I or a pharmaceutically suitable acid addition salt thereof A typical dose for adult patients amounts to 0 1 to 1000 mg of the compound of the formula I or a pharmaceutically suitable acid addition salt thereof, daily The above dose can be administered in one or more portions The actual dosage depends on many factors and is determined by the doctor

The pharmaceutical compositions of the invention are prepared by admixing a compound of the formula I or a pharmaceutically suitable acid addition salt thereof to one or more carπer(s), and converting the mixture obtained to a pharmaceutical composition in a manner known per se Useful methods are known from the literature, e g Remington's Pharmaceutical Sciences mentioned above One preferred subgroup of the pharmaceutical compositions of the invention contains an alkylpιperιdιnylbenzo[d]ιsoxazole derivative of the formula I, wherein Z represents a hydrogen atom or a hydroxy group R, X' and Y' mean, independently, a hydrogen atom, X forms together with Y a 5- to 6-membered aromatic or partially saturated isocyclic or heterocyclic ring, said latter ring containing one or more oxygen atom(s) and/or nitrogen atom(s) and/or sulfur atom(s) as the heteroatom and the isocyclic or heterocyclic ring can be substituted by a Cι- alkyl group or a Cι- alkoxy group, n has a value of 0 or 1 , or a pharmaceutically suitable acid addition salt thereof as the active ingredient

Within the above subgroup, especially preferred pharmaceutical compositions of the invention contain an alkylpιperιdιnyi-beπzo[d]ιsoxazole derivative of the formula I, wherein

Z represents a hydrogen atom or a hydroxy group, R, X' and Y' mean, independently, a hydrogen atom, X forms together with Y a benzene ring or a 5-membered aromatic or partially saturated heterocyclic ring containing two oxygen atoms or two nitrogen atoms and a sulfur atom as the heteroatom, n has a value of 0 or 1 , or a pharmaceutically suitable acid addition salt thereof as the active ingredient A further preferred subgroup of the pharmaceutical compositions of the invention contains an alkylpipeπdmyl- benzo[d]ιsoxazole derivative of the formula la, wherein

Z represents a hydrogen atom or a hydroxy group,

R stands for a hydrogen atom,

X' and Y' mean, independently, a hydrogen atom or a Cι_-4 alkoxy group, or

X' forms together with Y a 5- to 6-membered aromatic or partially saturated isocyclic or heterocyclic ring, said latter ring containing two oxygen atoms or a nitrogen atom as the heteroatom, and the isocyclic or heterocyclic ring is optionally fused with a benzene ring, n has a value of 0 or 1 , or a pharmaceutically suitable acid addition salt thereof as the active ingredient

Within the latter subgroup, especially preferred pharmaceutical compositions of the invention contain an alkylpipendinyl- benzo[d]ιsoxazole derivative of the formula la, wherein

Z represents a hydrogen atom or a hydroxy group,

R stands for a hydrogen atom

X' and Y' mean, independently, a hydrogen atom or a methoxy group, or X' forms together with Y' a benzene ring or pyrrol ring which latter is fused with a benzene ring, n has a value of 0 or 1 , or a pharmaceutically suitable acid addition salt thereof as the active ingredient Furthermore, the invention refers to a method of treatment in which a patient suffering from especially a disease of the central nervous system is treated with a non-toxic dose of an alkylpιperιdιnylbenzo[d]ιsoxazole derivative of the formula I or a pharmaceutically suitable acid addition salt thereof

In addition, the invention includes the use of an alkylpipeπdinyl- benzo[d]ιsoxazole derivative of the formula I or a pharmaceutically suitable acid addition salt thereof for the preparation of a pharmaceutical composition having psychotropic effect

The invention is further elucidated by means of the following Examples

Preparation of the starting compounds Preparation of starting compound of the formula II

1 ) 3-/1 -(3-Chloropropyl)pιperιdιne-4-yl/-6-fluorobenzo[d]- isoxazole

2.2 g (10 mmoles) of 6-fluoro-3-(pιperιdιne-4-yl)benzo[d]- isoxazole, 0 44 g (11 mmoles) of sodium hydroxide, 2 ml of water and 2 36 g (15 mmoles) of 1-bromo-3-chloropropane are stirred at room temperature for 3 days Then water is added to the mixture that is extracted twice with toluene The phase containing toluene is acidified to pH=1 with 15 % aqueous hydrochloric acid under cooling The aqueous phase is separated, pure toluene is added to it, and the mixture is made alkaline by the addition of 30 % aqueous sodium hydroxide The aqueous phase is extracted with toluene still twice The combined toluene phases are dried over anhydrous magnesium sulfate and evaporated Thus, 2 3 g (67 %) of the title product are obtained M p 74-76 °C

Preparation of starting compounds of the formula III

2) 5-Oxιranyimethoxybenzo[1 ,3]dιoxole

To a mixture of 1 38 g (10 mmoles) of 3,4-methylenedιoxy- phenol (sesamol), 2 5 ml of dimethyl sulfoxide 0 4 g (10 mmoles) of sodium hydroxide and 5 ml of water, 2 5 ml (33 mmoles) of epichlorohydπn are added, drop by drop, at room temperature and under argon atmosphere under stirring The reaction mixture is stirred at 25 °C for 48 hours then poured onto water, and extracted with ethyl acetate The organic phase is washed with water dried over anhydrous magnesium sulfate and evaporated Thus, 1 5 g (77 %) of the title product are obtained

3) 5-(2-Bromoethoxy)benzo[1 ,3]dιoxole

To a mixture of 1 38 g (10 mmoles) of sesamol, 3 5 ml (41 mmoles) of dibromoethane and 2 ml of water, a solution of 0 4 g (10 mmoles) of sodium hydroxide in 6 5 ml of water are added, drop by drop, at 100 °C under argon atmosphere in 3 hours The reaction mixture is stirred at 100 °C for 16 hours, then cooled, water is added, and the mixture is extracted twice with ethyl acetate The combined organic phases are washed with 20 % aqueous sodium hydroxide and water dried, and evaporated The crude product is subjected to chromatography on silica gel using chloroform as the eluent Thus, 1 5 g (62 %) of the title product are obtained

4) 5-Oxιranylmethoxybenzo[1 2 5]thιadιazoie

To a mixture of 1 52 g (10 mmoles) of 5-hydroxybenzo[1 2 5]- thiadiazole, 3 ml of dimethyl sulfoxide, 0 4 g (10 mmoles) of sodium hydroxide and 5 ml of water, 3 7 g (40 mmoles) of epichlorohydπn are added, drop by drop, at room temperature and under argon atmosphere under stirring The reaction mixture is stirred at 25 °C for 48 hours, then poured onto water and extracted with ethyl acetate The organic phase is washed with water, dried over anhydrous magnesium sulfate and evaporated The residue is suspended in a 1 1 mixture of n- hexane and diethyl ether then filtered The crude product obtained is purified by chromatography on silica gel using chloroform Thus, 1 4 g (67 %) of the title product are obtained M p 95-97 °C

5) 2-Methyl-6-oxιranylmethoxybenzoxazole

To a solution of 2 98 g (20 mmoles) of 6-hydroxy-2-methyl- benzoxazole in 25 ml of isopropanol a solution of 0 9 g (25 mmoles) of sodium hydroxide in 25 ml of water is added drop by drop, under ice cooling, and the mixture is stirred for 30 minutes Then, 6 17 g (66 7 mmoles) of epichlorohydrin are added and the reaction mixture is stirred at 40 °C for 3 5 hours The mixture is poured onto 200 ml of water, extracted twice using 100 ml of dichloromethane each time, the combined organic phases are dried and evaporated The crude product is subjected to chromatography on silica gel using chloroform as the eluent Thus, 2 91 g (71 %) of the title product are obtained

6) 2-Methyl-5-oxιranylmethoxybenzoxazole

To a solution of 2 98 g (20 mmoles) of 5-hydroxy-2- methylbenzoxazole in 25 ml of isopropanol, a solution of 0 9 g (25 mmoles) of sodium hydroxide in 25 ml of water are added, drop by drop, under ice cooling, and the mixture is stirred for 30 minutes Then, 6 17 g (66 7 mmoles) of epichlorohydrin are added and the reaction mixture is stirred at 40 °C for 3 hours The mixture is poured onto 200 ml of water and extracted twice with 100 ml of dichloromethane each time The combined organic solutions are dried and evaporated The crude product is subjected to chromatography on silica gel using a 20 1 mixture of chloroform and methanol Thus, 2 81 g (69 %) of the title product are obtained Example 1

1 -(Benzo[1 ,3]dιoxole-5-yloxy)-3-/4-(6-fluorobenzo[d]ιsoxazole-

3-yl)pιperιdιne-1-yl/propane-2-ol

1 1 g (5 mmoles) of 6-fluoro-3-(pιperιdιπe-4-yl) benzofd]- isoxazole and 0 97 g (5 mmoles) of 5-oxιranylmethoxybeπzo- [1 ,3]dιoxole are stirred in 25 ml of ethanol at room temperature for 3 days Then, the crystals in the reaction mixture are filtered and dried Thus, 1 50 g (72 %) of the title product are obtained M p 103-105 °C

Analysis for C₂₂H₂₃FN₂0₅ (414 437) calculated C 63 76 %, H 5 59 %, N 6 76 %, found C 63 45 %, H 5 61 %, N 6 75 %

Example 2

3-/1 -(3-Benzo[1 ,3]dιoxole-5-yloxypropyl)pιpeπdιne-4-yl/-6- fluorobenzo[d]ιsoxazole

1 56 g (5 mmoles) of 3-/1 -(3-chloropropyl)pιpeπdιne-4-yl/-6- fluorobenzo[d]ιsoxazoie, 0 79 g (5 mmoles) of sesamol and 1 38 g (10 mmoles) of potassium carbonate are heated under reflux in 4 ml of dimethylformamide for 5 minutes The reaction mixture is cooled, and 30 ml of water are added to it The mixture is stirred for an hour, the crystals precipitated are filtered, and washed with water The crude product is subjected to chromatography on silica gel using a 2 1 mixture of hexane and acetone as the eluent Thus, 1 66 g (83 %) of the title product are obtained M p 94-96 °C Analysis: for C₂₂H₂₃FN₂0₄ (398.438) calculated: C 66.32 %, H 5.82 %, N 7.03 %; found: C 66.22 %, H 5.83 %, N 6.99 %.

Example 3

3-/1-(2-Benzo[1 ,3]dioxole-2-yloxyethyl)piperidine-4-yl/-6-fluoro- benzo[d]isoxazole

1.43 g (6.5 moles) of 6-fluoro-3-piperidine-4-yl) benzo[d]- isoxazole, 1.21 g (5 mmoles) of 5-(2-bromoethoxy)benzo[1 ,3]- isoxazole and 1.38 g (10 mmoles) of potassium carbonate are heated under reflux in 20 ml of acetonitrile for 16 hours. The reaction mixture is cooled, filtered, and the mother liquor is evaporated. The evaporation residue is suspended in diethyl ether, and the crystals obtained are filtered. The crude product is recrystallized from 2-propanol. Thus, 1.5 g (78 %) of the title product are obtained. M.p.: 108-110 °C. Analysis: for C₂ιH₂ιFN₂0₄ (384.411 ) calculated: C 65.62 %, H 5.51 %, N 7.29 %; found: C 65.45 %, H 5.53 %, N 7.35 %.

Example 4

3-(Benzo[1 ,2,5]thiadiazole-5-yloxy)-1-/4-(6-fluoro benzofd]- isoxazole-3-yl)piperidine-1 -yl/propane-2-ol

1.1 g (5 mmoles) of 6-fluoro-3-(pipehdine-4-yl) beπzofd]- isoxazole and 1.04 g (5 mmoles) of 5-oxiranylmethoxybenzo- [1 ,2,5]thiadiazole are stirred in 30 ml of ethanol at room temperature for 3 days The crystals in the reaction mixture are filtered and dried Thus, 1 60 g (75 %) of the title product are obtained M p 142-144 °C

Analysis for C₂ιH₂₁FN₄O₃S (428 489) calculated C 58 87 %, H 4 94 %, N 13 08 % S 7 48 %, found C 58 69 %, H 5 16 %, N 12 82 %, S 7 37 %

Example 5

5-[3-/4-(6-Fluorobenzo[d]ιsoxazole-3-yl)pιpeπdιπe-1 -yl/- propoxy]beπzo[1 ,2,5]thιadιazole

1 70 g (6 mmoles) of 3-/1-(3-chloropropyl)pιperιdιπe-4-yl/-6- fluorobenzo[d]ιsoxazole, 0 76 g (5 mmoles) of 5-hydroxybenzo- [1 ,2,5]thιadιazole and 1 38 g (10 mmoles) of potassium carbonate are heated under reflux in 4 ml of dimethylformamide for 15 minutes The reaction mixture is cooled, 100 ml of water are added, the mixture is extracted three times with 50 ml of ethyl acetate each time The combined organic phases are washed three times with 50 ml of water each time, dried over anhydrous magnesium sulfate, and evaporated The crude product is subjected to chromatography on silica gel using a 3 1 mixture of hexane and acetone as the eluent Thus, 1 1 g (83 %) of the title product are obtained M p 125-127 °C Analysis for C₂ιH₂₁FN₄0₂S (412 490) calculated C 61 15 %, H 5 13 % N 13 58 %, S 7 77 %, found C 60 99 %, H 5 26 %, N 13 28 % S 7 80 % Example 6

1 -/4-(6-Fluorobenzo[d]ιsoxazole-3-yl)pιperιdιne-1 -yl/-3-

(naphthalene-2-yloxy)propane-2-ol

1 1 g (5 mmoles) of 6-fluoro-3-(pιpeπdιne-4-yl)benzo[d]- isoxazole and 1 0 g (5 mmoles) of 5-oxιranylmethoxybenzo-

[1 ,2,5]thιadιazole are stirred in 25 ml of ethanol at room temperature for 3 days The crystals in the reaction mixture are filtered the crude product is recrystallized from 2-propanol

Thus, 1 60 g (76 %) of the title product are obtained

M p 157-159 °C

Analysis for C₂₅H₂₅FN₂θ3 (420 488) calculated C 71 41 %, H 5 99 %, N 6 66 %, found C 71 11 %, H 5 88 %, N 6 61 %

Example 7

1 -/4-(6-Fluorobenzo[d]ιsoxazole-3-yl)pιperιdιne-1 -yl/-3-

(naphthalene-1-yloxy)propane-2-ol

1 1 g (5 mmoles) of 6-fluoro-3-(pιperιdιne-4-yl)benzo[d]- isoxazole and 1 15 g (5 mmoles) of 2-oxιranylmethoxy-7- methoxynaphthalene are stirred in 25 ml of ethanol at room temperature for 5 days Then the crystals in the reaction mixture are filtered Thus, 1 70 g (76 %) of the title product are obtained M p 135-137 °C Analysis for C₂₆H₂₇FN₂0₄ (450 514) calculated C 69 32 %, H 6 04 %, N 6 22 %, found C 68 92 %, H 5 92 %, N 6 05 %

Example 8

6-Fluoro-3-[1 -/3-(7-methoxynaphthaleπe-2-yloxy)propyl/- pιperιdιne-4-yl]benzo[d]ιsoxazole

1 56 g (5 mmoles) of 3-/1 -(3-chloropropyl)pιperιdιne-4-yl/-6- fluorobenzo[d]ιsoxazole, 0 87 g (5 mmoles) of 7-methoxy-2- naphthol and 1 38 g (10 mmoles) of potassium carbonate are heated in 5 ml of dimethylformamide under reflux for 15 minutes The reaction mixture is cooled, and 25 ml of water are added to it After 1 hour's stirring, the crystals formed are filtered and washed with water The crude product is recrystallized from 2-propanol Thus, 1 4 g (65 %) of the title compound are obtained M p 118-120 °C Analysis for C₂₆H₂₇FN₂θ₃ (434 515) calculated C 71 87 %, H 6 26 %, N 6 45 %, found C 71 36 %, H 6 31 %, N 6 28 %

Example 9

1 -/4-(6-Fluorobenzo[d]ιsoxazole-3-yl)pιperιdιne-1 -yl/-3-(6- methoxynaphthalene-1-yloxy)propane-2-ol

1 1 g (5 mmoles) of 6-fluoro-3-(pιperιdιne-4-yl)benzo[d]- isoxazole and 1 15 g (5 mmoles) of 2-oxιranylmethoxy-6- methoxynaphthalene are stirred in 25 mi of ethanol at room temperature for 5 days Then the crystals in the reaction mixture are filtered Thus, 1 77 g (79 %) of the title product are obtained M p 146-148 °C Analysis for C₂₆H₂₇FN₂0₄ (450 514) calculated C 69 32 %, H 6 04 %, N 6 22 %, found C 68 83 %, H 5 95 %, N 6 02 %

Example 10

6-Fluoro-3-[1-/3-(6-methoxynaphth-2-yloxy)propyl/pιperιdιne-

4-yl]benzo[d]ιsoxazole

1 56 g (5 mmoles) of 3-/1 -(3-chloropropyl)pιpeπdιne-4-yl/-6- fluorobenzo[d]ιsoxazole, 0 87 g (5 mmoles) of 7-methoxy-2- naphthol and 1 18 g (10 mmoles) of potassium carbonate are heated in 5 ml of dimethylformamide under reflux for 15 minutes The reaction mixture is cooled, and 25 ml of water are added to it After 1 hour's stirring, the crystals formed are filtered and washed with water The crude product is recrystallized from 2-propanol Thus, 1 5 g (69 %) of the title product are obtained M p 140-142 °C Analysis for C₂6H₂₇FN₂0₃ (434 515) calculated C 71 87 %, H 6 26 %, N 6 45 %, found C 71 30 %, H 6 30 %, N 6 26 %

Example 11

1 -/4-(6-Fluorobeπzo[d]ιsoxazole-3-yl)pιperιdιne-1 -yl/-3-(2- methylbenzoxazole-6-yloxy)propane-2-ol

A solution of 1 51 g (6 86 mmoles) of 6-fluoro-3-pιpeπdιne-4-yl- benzo[d]ιsoxazole and 1 40 g (6 86 mmoles) of 2-methyl-6- oxiranylmethoxybenzoxazole in 50 ml of isopropanol is heated under reflux for 3 hours The reaction mixture is evaporated, and the crude product is subjected to chromatography on silica gel using a 20 1 mixture of chloroform and methanol as the eluent The fractions containing the product are evaporated, the residue is suspended in ether, filtered, and dried Thus,

1 70 g (58 %) of the title product are obtained

M p 136-138 °C

Analysis for C₂₃H₂₄FN₃0₄ (425 464) calculated C 64 93 %, H 5 69 %, N 9 88 %, found C 63 91 %, H 5 65 %, N 9 80 %

Example 12

6-Fluoro-3-[1 -/3-(2-methylbenzoxazole-6-yloxy)propyl/- pιperιdιne-4-yl]benzo[d]ιsoxazole

A solution of 1 56 g (5 mmoles) of 3-/1 -(3-chloropropyl)- pιperιdιne-4-yl/-6-fluorobeπzo[d]ιsoxazole, 0 75 g (5 mmoles) of 6-hydroxy-2-methylbenzoxazole and 0 83 g (6 mmoles) of potassium carbonate in 50 ml of dimethylformamide are heated under reflux for 30 minutes The reaction mixture is poured onto 250 ml of water, then extracted three times with 100 ml of ethyl acetate each time The combined ethyl acetate phases are extracted twice using 100 ml of water each time, dried, and evaporated The crude product is subjected to chromatography in silica gel using a 20 1 mixture of chloroform and methanol as the eluent The free base is dissolved in ether and reacted with ether containing hydrogen chloride to obtain the hydrochloride The precipitated crystals are filtered, washed with some ether, and dried Thus, 1 46 g (66 %) of the title product are obtained

M p 235-238 °C

Analysis for C₂3H₂₅CIFN₃θ3 calculated C 61 95 %, H 5 65 %, CI 7 95 %, N 9 42 %, found C 60 93 %, H 5 55 %, CI 7 93 %, N 9 26 %

Example 13

1 -/4-(6-Fluorobenzo[d]ιsoxazole-3-yl)pιperιdιne-1 -yl/-3-(2- methylbenzoxazole-5-yloxy)propane-2-ol

A solution of 1 10 g (5 mmoles) of 6-fluoro-3-(pιperιdιne-4-yl)- benzo[d]ιsoxazole and 1 02 g (5 mmoles) of 2-methyl-5- oxiranylmethoxybenzoxazole in 50 ml of isopropanol is heated under reflux for 4 hours The reaction mixture is evaporated, and the crude product is subjected to chromatography on silica gel using a 20 1 mixture of chloroform and methanol as the eluent The fractions containing the product are evaporated, the residue is suspended in diisopropyl ether, filtered, and dried Thus, 1 59 g (75 %) of the title product are obtained M p 120-124 °C

Analysis for C₂₃H₂ FN₃0₄ (425 464) calculated C 64 93 % H 5 69 %, N 9 88 %, found C 62 36 %, H 5 60 %, N 9 49 %

Example 14

2S-(+)-1 -(Benzo[1 ,3]dιoxole-5-yloxy)-3-/4-(6-fluorobenzo[d]- ιsoxazole-3-yl)pιperιdιne-1 -yl/propane-2-ol 2 4 g (11 mmoles) of 6-fluoro-3-(pιperιdιne-4-yl) benzo[d]- isoxazole and 2 12 g (11 mmoles) of (S)-(-)-5-oxιranylmethoxy- benzo[1 ,3]dιoxole are stirred in 46 ml of ethanol at room temperature for 3 days Then, the crystals in the reaction mixture are filtered and dried The crystals obtained are subjected to chromatography on silica gel using a 59 1 mixture of chloroform and methanol as the eluent The substance purified by chromatography is recrystallized from 20 mi of isopropanol Thus, 2 45 g (54 %) of the title product are obtained M p 1 10-112 °C [α]_D ²⁰ = 15 3 (c=1 chloroform) Analysis for C₂₂H₂₃FN₂0₅ (414 437) calculated C 63 76 %, H 5 99 %, N 6 76 %, found C 63 44 %, H 5 57 %, N 6 67 %

Example 15

2R-(-)-Benzo[1 ,3]dιoxole-5-yloxy)-3-/4-(6-fluorobenzo[d]- ιsoxazole-3-yl)pιperιdιne-1 -yl/propane-2-ol

2 61 g (11 9 mmoles) of 6-fluoro-3-(pιperιdιne-4-yl) benzo[d]- isoxazole and 2 3 g (11 9 mmoles) of (R)-(+)-5-oxιranyl- methoxybenzo[1 ,3]dιoxole are stirred in 50 ml of ethanol at room temperature for 3 days Then, the crystals in the reaction mixture are filtered and dried The crystals obtained are subjected to chromatography on silica gel using a 39 1 mixture of chloroform and methanol as the eluent The substance purified by chromatography is recrystallized from 17 ml of isopropanol Thus, 2 72 g (55 %) of the title product are obtained M p 1 10-112 °C [α]_D ²⁰ = -16 1 (c=1 , chloroform) Analysis for C₂₂H₂₃FN₂θ5 (414 437) calculated C 63 76 %, H 5 59 %, N 6 76 % found C 63 49 %, H 5 65 %, N 6 65 %

Example 16

6-Fluoro-3-[1 -/2-(7-methoxynaphthalene-2-yloxy)ethyl/- pιperιdιne-4-yl]benzo[d]ιsoxazole

1 43 g (6 5 mmoles) of 6-fluoro-3-(pιpeπdιne-4-yl) benzo[d]- isoxazole, 1 32 g (5 mmoles) of 2-(2-bromoethoxy)-7-methoxy- naphthalene and 2 76 g (10 mmoles) of potassium carbonate are heated in 40 ml of acetonitrile under reflux for 16 hours Then, the reaction mixture is cooled, filtered and the mother liquor is evaporated The evaporation residue is subjected to chromatography on silica gel using a 19 1 mixture of chloroform and methanol as the eluent Thus, 1 7 g (81 %) of the title product are obtained M p 114-116 °C Analysis for C_2SH₂₅FN₂0₃ (420 49) calculated N 6 66 %, found N 6 56 %

Example 17

6-Fluoro-3-[1-/2-(2-methylbenzoxazole-6-yloxy)ethyl/pιperιdιne-

4-yl]benzo[d]ιsoxazole

0 60 g (4 mmoles) of 6-fluoro-3-(pιpeπdιne-4-yl)benzo[d]- isoxazole, 1 13 g (4 mmoles) of 3-/1-(2-chloroethyl)pιperιdιne-4- yi/-6-fiuorobenzo[d]ιsoxazole and 0 69 g (5 mmoles) of potassium carbonate are heated in 30 ml of dimethylformamide under reflux for 10 minutes Then, the mixture is poured onto 200 ml of water, extracted three times using 50 ml of dichloromethane each time, and the combined organic phases are extracted with water and potassium hydroxide solution The organic solution is dried, evaporated, and subjected to chromatography on a short column using a 20 1 mixture of dichloromethane and methanol as the eluent Thus, 0 83 g (52 %) of the title compound are obtained M p 121 -124 °C Analysis for C₂₂H₂ FN₃0₃ (395 437) calculated C 66 82 %, H 5 61 %, N 10 63 %, found C 66 41 %, H 5 70 %, N 10 62 %

Example 18

1 -(2,3-Dιhydrobenzo[1 ,4]dιoxιne-5-yloxy)-3-/4-(6-fluorobenzo-

[d]ιsoxazole-3-yl)pιperιdιne-1 -yl/propane-2-ol

1 1 g (5 mmoles) of 6-fIuoro-3-(pιpeπdιne-4-yl)benzo[d]- isoxazole and 1 1 g (5 mmoles) of 5-oxιranylmethoxy-2,3- dιhydrobenzo[1 ,4]dιoxιπe are stirred in 30 ml of ethanol at room temperature for 3 days Then, the reaction mixture is evaporated, and the residue is recrystallized from a 1 1 mixture of ethyl acetate and diisopropyl ether Thus, 1 40 g (65 %) of the title product are obtained M p 1 15-1 17 °C Analysis for C₂₃H₂₅FN₂0₅ (428 465) calculated C 64 48 %, H 5 88 %, N 6 54 %, found C 64 38 %, H 5 88 %, N 6 51 % Example 19

1 -(2,3-Dιhydrobenzo[1 ,4]dιoxιne-5-yloxy)-3-/4-(6-fluorobenzo-

[d]ιsoxazole-3-yl)pιperιdιne/ hydrochloride

1 56 g (5 mmoles) of 3-/1 -(3-chloropropyl)pιperιdιne-4-yl/-6- fluorobenzo[d]ιsoxazole, 0 76 g (5 mmoles) of 2,3-dιhydro- benzo[1 ,4]dιoxιne-5-ol and 1 38 g (10 mmoles) of potassium carbonate are heated in 5 ml of dimethylformamide under reflux for 30 minutes Then, the reaction mixture is cooled and water is added to it The mixture is extracted twice with ethyl acetate The collected organic phases are washed with 20 % aqueous sodium hydroxide and water, dried, and evaporated The crude product is subjected to chromatography on silica gel using a 39 1 mixture of chloroform and methanol The substance obtained is dissolved in diethyl ether, and, to the solution, diethyl ether containing hydrogen chloride is added The crystals precipitated are filtered, washed with ether, and dried Thus 1 9 g (83 %) of the title product are obtained M p 217-219 °C

Analysis for C₂₃H₂₆CIFN₂0₄ (448 926) calculated C 61 54 %, H 5 84 %, N 6 24 %, CI 7 90 %, found C 61 56 %, H 5 75 %, N 6 36 %, CI 7 86 %

Example 20

3-[1-/2-(2,3-Dιhydrobenzo[1 ,4]dιoxιne-5-yloxy)ethyl/pιperιdιne- 4-yl]6-fluorobenzo[d]ιsoxazole hydrochloride

1 43 g (6 5 mmoles) of 6-fluoro-3-(pιperιdιne-4-yl)benzo[d]- isoxazole, 1 21 g (5 mmoles) of 5-(2-bromoethoxy)-2,3-dιhydro- benzo[1 ,4]dιoxιne and 2 76 g (20 mmoles) of potassium carbonate are heated in 35 ml of acetonitrile under reflux for 3 hours Then, the reaction mixture is cooled, filtered, the mother liquor is evaporated, and the evaporation residue is subjected to chromatography on silica gel using a 59 1 mixture of chloroform and methanol as the eluent The substance obtained is dissolved in diethyl ether, and, to the mixture, diethyl ether containing hydrogen chloride is added The crystals precipitated are filtered, washed with ether, and dried Thus, 1 6 g (74 %) of the title product are obtained M p 202-204 °C

Analysis for C₂₂H₂₄CIFN₂0₄ (434 899) calculated C 60 76 %, H 5 56 %, N 6 44 %, CI 8 15 % found C 60 37 %, H 5 55 %, N 6 54 %, CI 8 05 %

Example 21

1 -/4-(6-Fluorobeπzo[d]ιsoxazole-3-yl)pιperιdιne-1 -yl/-3-

(naphthalene-1 -yloxy)propane-2-ol

A solution of 1 10 g (5 mmoles) of 6-fluoro-3-(pιperιdιne-4-yl)- benzo[d]ιsoxazole and 1 0 g (5 mmoles) of 2-(naphthalene-1 - yloxymethyl)oxιrane in 20 ml of ethanol is stirred at room temperature for 24 hours, then heated under reflux for 2 hours The reaction mixture is evaporated and the residue is boiled in a 1 1 mixture of ethyl acetate and hexane After cooling, the crystals precipitated are filtered, washed with some ether, and dried The crude product is dissolved in a 8 1 mixture of dichloromethane and methanol, filtered through a small amount of silica gel, and evaporated Thus, 1 24 g (59 %) of the title compound are obtained M p 149-151 °C Analysis for C ₅H₂₅FN₂0₃ (420 488) calculated C 71 41 %, H 5 99 %, N 6 66 %, found C 69 46 %, H 6 15 %, N 6 50 %

Example 22

6-Fluoro-3-/1 -(3-πaphthalene-1 -yloxypropyl)pιpeπdιne-4-yl/- benzo[d]ιsoxazole hydrochloride

A mixture of 2 57 g (10 mmoles) of 6-fluoro-3-(pιpeπdιne-4-yl)- benzo[d]ιsoxazole hydrochloride, 2 59 g (10 mmoles) of 1 -(2- bromopropoxy)naphthalene, 3 45 g (25 mmoles) of potassium carbonate and 100 ml of acetonitrile is heated under reflux for 4 hours After cooling, the reaction mixture is filtered, washed with some acetonitrile and evaporated The crude product is subjected to chromatography on silica gel using chloroform as the eluent 2 50 g of product are obtained 1 g of which is dissolved in ether To the solution obtained, ether containing hydrogen chloride is added to obtain the hydrochloride The crystals precipitated are filtered, washed with ether and dried Thus, 0 70 g (41 %) of the title product are obtained p 215-223 °C

Analysis for C₂₅H₂₆CIFN₂0₂ (440 950) calculated C 68 10 %, H 5 94 %, N 6 35 %, CI 8 04 %, found C 68 13 %, H 6 06 %, N 6 33 %, CI 7 44 % Example 23

6-Fluoro-3-/1 -(2-naphthaleπe-1 -yloxypropyl)pιperιdιne-4-yl/- benzo[d]ιsoxazole

A mixture of 2 20 g (10 mmoles) of 6-fluoro-3-(pιpeπdιne-4-yl)- benzo[d]ιsoxazole, 2 51 g (10 mmoles) of 1 -(2-bromoethoxy)- naphthalene, 1 38 g (10 mmoles) of potassium carbonate and 50 ml of acetonitrile is heated under reflux for 5 hours After cooling, the reaction mixture is filtered, washed with some acetonitrile The crystals that remained on the filter are suspended in ether, filtered, the filtrate is evaporated Thus, 1 4 g (35 %) of the title product are obtained M p 99-100 °C Analysis for C₂₄H₂₃FN₂0₂ (390 462) calculated C 73 83 %, H 5 94 %, N 7 17 %, found C 73 90 %, H 6 01 %, N 7 21 %

Example 24

1 -(9H-Carbazole-2-yloxy)-3-/4-(6-fluorobenzo[d]ιsoxazole-3-yl)- pιperιdιne-1 -yl/propane-2-ol fumarate

1 1 g (5 mmoles) of 6-fluoro-3-(pιperιdιne-4-yl) benzo[d]- isoxazole and 1 2 g (5 mmoles) of 4-oxιranylmethoxy-9H- carbazole are stirred in 50 ml of ethanol at room temperature for 3 days Then, the reaction mixture is evaporated, and the residue is subjected to chromatography on silica gel using a 39 1 mixture of chloroform and methanol as the eluent The base obtained is dissolved in ethanol, and, to the solution, an equimolar quantity of fumaric acid in ethanol is added The crystals obtained are filtered and dried Thus, 1 5 g (52 %) of the title product are obtained M p 139-140 °C Analysis for C₃ιH₃oFN₃0₇ (575 599) calculated C 64 69 %, H 5 25 %, N 7 30 %, found C 64 86 %, H 5 24 %, N 7 33 %

Example 25

4-[3-/4-(6-Fluorobenzo[d]ιsoxazole-3-yl)pιperιdιπe-1 -yl/- propoxy]-9H-carbazole

A mixture of 1 71 g (5 5 mmoles) of 3-/1-(3-chloropropyl)- pιperιdιne-4-yl/-6-fluorobeπzo[d]ιsoxazole, 0 91 g (5 mmoles) of 9H-carbazole-4-ol, 30 ml of 2-propanol, 6 ml of water and 0 24 g (0 006 moles) of sodium hydroxide is stirred at room temperature under argon for 30 minutes Then, 1 71 g (5 5 mmoles) of 3-/1 -(3-chloropropyl)pιperιdιne-4-yl/-6-fluoro- benzo[d]ιsoxazole are added, and the reaction mixture is heated to 50 °C and stirred at this temperature for 48 hours Then the reaction mixture is evaporated, and the residue is subjected to chromatography on silica gel using a 2 1 mixture of ethyl acetate and hexane as the eluent Thus, 1 4 g (63 %) of the title product are obtained M p 145-147 °C Analysis for C₂₇H₂₆FN₃0₂ (443 526) calculated C 73 12 %, H 5 91 %, N 9 47 %, found C 72 97 %, H 5 88 %, N 9 43 % Example 26

3-[2-/4-(6-Fluorobenzo[d]ιsoxazole-3-yl)pιperιdιne-1 -yl/-ethoxy]-

9H-carbazole

A mixture of 2 42 g (11 mmoles) of 6-fluoro-3-pιperιdιne-4-yl- benzo[d]ιsoxazole, 2 90 g (10 mmoles) of 4-(2-bromoethoxy)- 9H-carbazole, 2 02 g (20 mmoles) of triethylamine and 40 ml of acetonitrile is heated under reflux for 2 hours Then the reaction mixture is cooled, filtered and the mother liquor is evaporated The evaporation residue is subjected to chromatography on silica gel using a 79 1 mixture of chloroform and methanol as the eluent Thus, 2 7 g (63 %) of the title product are obtained M p 140-142 °C Analysis for C₂₆H₂₄FN₃0₂ (429 498) calculated C 72 71 %, H 5 63 %, N 9 78 %, found C 72 36 %, H 5 56 %, N 7 49 %

Example 27

1-/4-(6-Fluorobenzo[d]ιsoxazole-3-yl)pιperιdιne-4-yl/-3-(2- methoxyphenoxy)propane-2-ol

A solution of 1 20 g (5 45 mmoles) of 6-fluoro-3-(pιperιdιne-4- yl)benzo[d]ιsoxazole and 0 98 g (5 45 mmoles) of 2-(2- methoxyphenoxymethyl)oxιrane in 20 ml of ethanol is stirred at room temperature for 6 hours, then allowed to stand After 48 hours, the crystals precipitated are filtered, washed with some ethanol, and dried Thus, 1 68 g (77 %) of the title product are obtained M p 1 14-117 °C Analysis for C₂₂H₂₅FN₂0₄ (400 454) calculated C 65 99 % H 6 29 %, N 7 00 %, found C 66 30 %, H 6 41 %, N 6 80 %

Example 28

6-Fluoro-3-[1 -/2-(2-methoxyphenoxy)ethyl/pιperιdιne-4-yl]- benzo[d]ιsoxazole hydrochloride

A mixture of 2 56 g (10 mmoles) of 6-fluoro-3-(pιpeπdιne-4-yl)- benzo[d]ιsoxazole, 2 31 g (10 mmoles) of 1 -(2-bromoethoxy)-2- methoxybenzene, 3 45 g (25 mmoles) of potassium carbonate and 200 ml of acetonitrile is heated under reflux for 20 hours, then cooled, filtered, washed with acetonitrile, and evaporated The residue is dissolved in ethyl acetate, and extracted 5 times with 100 ml of 10 % hydrochloric acid each time The acidic phase is made alkaline, and extracted with dichloromethane The crude product is subjected to chromatography on a short column containing silica gel and using a 12 1 mixture of chloroform and methanol as the eluent The base obtained is stirred in diethyl ether filtered, then diethyl ether containing hydrogen chloride is added to it The crystals precipitated are filtered, washed with ether, and dried Thus, 2 10 g (52 %) of the title product are obtained M p 152-154 °C Analysis for C₂ιH₂₄CIFN₂0₃ (406 888) calculated C 61 99 %, H 5 95 %, N 5 95 %, CI 8 71 %, found C 61 41 % H 5 87 %, N 5 87 %, CI 8 53 % Example 29

1 -/4-(6-Fluorobenzo[d]ιsoxazole-3-yl)pιperιdιne-1 -yl/-3-(2- ιsopropoxyphenoxy)propane-2-ol

A solution of 1 10 g (5 mmoles) of 6-fluoro-3-(pιpeπdιne-4-yl)- benzo[d]ιsoxazole and 1 04 g (5 mmoles) of 2-(2-ιsopropoxy- phenoxymethyl)oxιrane in 50 ml of isopropanol is heated under reflux for 6 hours After cooling, the mixture is evaporated The crude product is suspended in diisopropyl ether, and filtered The substance obtained is subjected to chromatography on a short column containing silica gel and using a 20 1 mixture of dichloromethane and methanol as the eluent Thus, 1 30 g (57 %) of the title product are obtained M p 89-92 °C Analysis for C₂₄H₂₉FN₂0₄ (428 508) calculated C 67 27 %, H 8 82 %, N 6 54 %, found C 67 30 %, H 6 81 %, N 6 50 %

Example 30

6-Fluoro-3-[1-/3-(2-ιsopropoxyphenoxy)propyl/pιpeπdιne-4-yl]- benzo[d]ιsoxazole hydrochloride

A mixture of 1 48 g (5 mmoles) of 3-/1 -(3-chloropropyl)- pιperιdιne-4-yl/-6-fluorobenzo[d]ιsoxazole, 0 76 g (5 mmoles) of 2-ιsopropoxyphenol, 0 83 g (6 mmoles) of potassium carbonate and 30 ml of dimethylformamide is heated under reflux for 20 minutes, then poured onto water The mixture is extracted with dichloromethane, the organic phase is extracted several times with water and aqueous sodium hydroxide solution, then dried and evaporated The crude product is subjected to chromatography on silica gel using a 20 1 mixture of dichloromethane and methanol as the eluent The base obtained is dissolved in diethyl ether, and, to the solution, isopropanol containing hydrogen chloride is added The crystals precipitated are filtered, washed with ether, and dried Thus, 1 18 g (53 %) of the title product are obtained M p 130-140 °C

Analysis for C₂₄H₂₉FN₂0₄ (428 508) calculated N 6 54 %, CI 7 90 %, found N 6 50 % CI 7 64 %

Example 31

6-Fluoro-3-[1 -/2-(2-ιsopropoxyphenoxy)ethyi/pιperιdιne-4-yl]- benzo[d]ιsoxazole hydrochloride

A mixture of 0 85 g (3 mmoles) of 3-/1 -(2-chloroethyl)pιperιdιne- 4-yl/-6-fluorobenzo[d]ιsoxazole, 0 46 g (3 mmoles) of 2- isopropoxyphenol, 0 55 g (4 mmoles) of potassium carbonate and 20 ml of dimethylformamide is heated under reflux for 30 minutes, then poured onto water The mixture is extracted with dichloromethane, the organic phase is extracted several times with water and aqueous sodium hydroxide solution, then dried and evaporated The crude product is subjected to chromatography on silica gel using a 20 1 mixture of dichloromethane and methanol as the eluent The base obtained is dissolved in diethyl ether, and, to the solution, isopropanol containing hydrogen chloride is added The crystals precipitated are filtered, washed with ether, and dried Thus,

0 55 g (42 %) of the title product are obtained M p 169-179 °C

Analysis for C₂₃H₂₆CIFN₂0₃ (434 943) calculated C 63 52 %, H 6 49 %, N 6 44 % CI 8 15 %, found C 63 12 %, H 6 54 %, N 6 38 %, CI 8 05 %

Example 32

1 -/4-(6-Fluorobenzo[d]ιsoxazole-3-yl)pιperιdιne-1 -yl/-3-(4- chloronaphthalene-1 -yloxy)propane-2-ol hydrochloride

A solution of 0 66 g (3 mmoles) of 6-fluoro-3-(pιperιdιne-4-yl)- benzo[d]ιsoxazole and 0 70 g (3 mmoles) of 2-(4-chloro- naphthalene-1-yloxymethyl)oxιrane in 30 ml of isopropanol is heated under reflux for 3 hours After cooling, the mixture is evaporated The crude product is subjected to chromatography on a short column containing silica gel and using a 20 1 mixture of chloroform and methanoi as the eluent The base obtained is dissolved in a mixture of diethyl ether and isopropanol, and, to the solution, isopropanol containing hydrogen chloride is added The crystals precipitated are filtered, washed with ether, and dried Thus, 1 01 g (71 %) of the title product are obtained M p 186-214 °C

Analysis for C₂₅H₂₅CI₂FN₂θ3 (491 394) calculated C 61 1 1 %, H 5 13 %, N 5 70 %, CI 14 43 % found C 60 80 %, H 5 15 %, N 5 50 %, CI 14 26 % Example 33

3-[1-/3-(4-Chloronaphthalene-1 -yloxy)propyl/pιperιdιne-4-yl]-6- fluorobenzo[d]ιsoxazole hydrochloride

A mixture of 1 48 g (5 mmoles) of 3-/1 -(3-chloropropyl)- pιperιdιne-4-yl/-6-fluorobenzo[d]ιsoxazole, 0 89 g (5 mmoles) of 4-chloro-1-naphthol, 0 70 g (5 mmoles) of potassium carbonate and 25 ml of dimethyl formamide is heated under reflux for 20 minutes, then poured onto water The mixture is extracted with ethyl acetate, the organic phase is extracted several times with water and aqueous sodium hydroxide solution, then dried and evaporated The crude product is subjected to chromatography on silica gel using a 20 1 mixture of dichloromethane and methanol The base obtained is dissolved in diethyl ether, and, to the solution, isopropanol containing hydrogen chloride is added The crystals precipitated are filtered washed with ether and dried Thus, 0 49 g (21 %) of the title product are obtained M p 208-211 °C

Analysis for C₂₅H₂₅CI₂FN₂0₂ (475 395) calculated C 63 16 %, H 5 30 %, N 5 89 %, CI 14 92 %, found C 62 88 %, H 5 32 %, N 5 92 %, CI 14 82 %

Example 34

3-[1-/2-(4-Chloronaphthalene-1 -yloxy)ethyl/pιperιdιne-4-yl]-6- fluorobenzo[d]ιsoxazole hydrochloride

A mixture of 0 85 g (3 mmoles) of 3-/1 -(2-chloroethyl)pιperιdιne- 4-yl/-6-fluorobenzo[d]ιsoxazole, 0 54 g (3 mmoles) of 4-chloro- 1-naphthol, 0 55 g (4 mmoles) of potassium carbonate and 20 ml of dimethylformamide is heated under reflux for 10 minutes, then poured onto water The mixture is extracted with dichloromethane, the organic phase is extracted several times with water and aqueous sodium hydroxide solution, then dried and evaporated The crude product is subjected to chromatography on silica gel using a 20 1 mixture of dichloromethane and methanol The base obtained is dissolved in diethyl ether, and, to the solution, isopropanol containing hydrogen chloride is added The crystals precipitated are filtered washed with ether and dried Thus, 0 61 g (44 %) of the title product are obtained M p 235-238 °C

Analysis for C₂₄H₂₃CI₂FN₂0₂ (461 368) calculated C 62 48 %, H 5 02 %, N 6 07 %, CI 15 37 %, found C 62 28 %, H 5 08 %, N 6 03 %, CI 15 23 %

Example 35

1 -/4-(6-Fluorobenzo[d]ιsoxazole-3-yl)pιperιdιne-1 -yl/-3-(4- methoxynaphthaiene-1-yloxy)propane-2-ol

A solution of 0 66 g (3 mmoles) of 6-fluoro-3-(pιperιdιne-4-yl)- benzo[d]ιsoxazole and 0 69 g (3 mmoles) of 2-(4-methoxy- naphthalene-1-yloxymethyl)oxιrane in 30 ml of isopropanol is heated under reflux for 9 hours After cooling, the mixture is evaporated The crude product is subjected to chromatography on a short column containing silica gel and using a 20 1 mixture of chloroform and methanol as the eluent The oily substance obtained is stirred in diisopropyl ether The crystals formed are filtered, washed with ether, and dried Thus, 0 52 g (42 %) of the title product are obtained

M p 103-105 °C

Analysis for C₂₆H₂₇FN₂0₄ (491 394) calculated C 69 32 %, H 6 04 %, N 6 22 %, found C 68 97 %, H 6 09 %, N 6 03 %

Example 36

6-Fluoro-3-[1 -/3-(4-methoxynaphthalene-1 -yloxy)propyl/- pιperιdιne-4-yl]beπzo[d]ιsoxazole hydrochloride

A mixture of 1 18 g (4 mmoles) of 3-/1 -(3-chloropropyl)- pιperιdιne-4-yl/-6-fluorobenzo[d]ιsoxazole, 0 70 g (4 mmoles) of 4-methoxy-1 -naphthol, 0 70 g (5 mmoles) of potassium carbonate and 30 ml of dimethylformamide is heated under reflux for 30 minutes, then poured onto water The mixture is extracted with dichloromethane, the organic phase is extracted several times with water and aqueous sodium hydroxide solution, then dried and evaporated The crude product is subjected to chromatography on silica gel using a 20 1 mixture of dichloromethane and methanol as the eluent The base obtained is dissolved in diethyl ether, and, to the solution, isopropanol containing hydrogen chloride is added The precipitated crystals are filtered, washed with ether, and dried Thus, 0 45 g (24 %) of the title product are obtained M p 199-203 °C Analysis for C₂₆H₂₈CIFN₂0₃ (470 976) calculated C 66 31 %, H 5 99 %, N 5 95 %, CI 7 53 %, found C 66 41 %, H 6 01 %, N 5 83 %, CI 7 46 %

Example 37

6-Fluoro-3-[1 -/2-(4-methoxynaphthalene-1 -yloxy)ethyl/- pιperιdιne-4-yl]benzo[d]ιsoxazole

A mixture of 0 43 g (1 96 mmoles) of 6-fluoro-3-(pιpeπdιne-4- yl)-benzo[d]ιsoxazole, 0 55 g (1 96 mmoles) of 1 -(2-bromo- ethoxy)-4-methoxynaphthalene, 0 41 g (3 mmoles) of potassium carbonate and 30 ml of acetonitrile is heated under reflux for 6 hours After cooling, the reaction mixture is filtered washed with acetonitrile, and evaporated The crude product is recrystallized twice from ethanol Thus, 0 62 g (76 %) of the title product are obtained M p 109-113 °C Analysis for C₂₅H₂₅FN₂0₃ (491 394) calculated C 71 41 %, H 5 99 %, N 6 66 %, found C 71 07 % H 6 02 %, N 6 64 %

Example 38

1 -/4-(6-Fluorobenzo[d]ιsoxazole-3-yl)pιperιdιne-1 -yl/-3-(7- fiuoronaphthalene-1 -yloxy)propane-2-ol hydrochloride

A solution of 0 66 g (3 mmoles) of 6-fluoro-3-(pιpeπdιne-4-yl)- benzo[d]ιsoxazole and 0 69 g (3 mmoles) of 2-(7-fluoro- naphthalene-1 -yloxymethyl)oxιrane in 20 ml of isopropanol is heated under reflux for 3 hours After cooling, the reaction mixture is evaporated The crude product is subjected to chromatography on silica gel using a 20 1 mixture of dichloromethane and methanol as the eluent The oil obtained is dissolved in ether, and, to the solution, isopropanol containing hydrogen chloride is added The crystals precipitated are filtered, washed with ether, and dried Thus,

0 68 g (48 %) of the title product are obtained

M p 198-212 °C

Analysis for C₂₅H₂₅CIF₂N₂0₃ (474 939) calculated C 63 22 %, H 5 31 % N 5 90 %, CI 7 46 %, found C 62 48 %, H 5 46 %, N 5 63 %, CI 7 58 %

Example 39

6-Fluoro-3-[1 -/3-(7-fluoronaphthalene-1 -yloxy)propyl/- pιperιdιne-4-yl]benzo[d]ιsoxazole hydrochloride

A mixture of 1 48 g (5 mmoles) of 3-/1 -(3-chloropropyl)- pιperιdιne-4-yl/-6-fluorobenzo[d]ιsoxazole, 0 81 g (5 mmoles) of 7-fluoro-1 -naphthol, 0 83 g (6 mmoles) of potassium carbonate and 20 ml of dimethylformamide is heated under reflux for 40 minutes, then poured onto water The mixture is extracted with ethyl acetate, the organic phase is extracted several times with water and aqueous sodium hydroxide solution, then dried, and evaporated The crude product is subjected to chromatography on silica gel using a 20 1 mixture of ethyl acetate and methanol as the eluent The base obtained is dissolved in diethyl ether, and to the solution, ether containing hydrogen chloride is added The crystals precipitated are filtered, washed with ether and dried Thus, 0 91 g (40 %) of the title product are obtained M p 224-227 °C

Analysis for C₂₅H₂₅CIF₂N₂0₂ (458 940) calculated C 65 43 %, H 5 49 %, N 6 10 %, CI 7 72 %, found C 65 38 %, H 5 51 %, N 6 04 %, CI 7 71 %

Example 40

6-Fluoro-3-[1 -/2-(7-fluoroπaphthalene-1 -yloxy)ethyl/-pιperιdιne-

4-yl]benzo[d]ιsoxazole

A mixture of 0 88 g (4 mmoles) of 6-fluoro-3-(pιperιdιne-4-yl)- benzo[d]ιsoxazole, 1 07 g (3 98 mmoles) of 1 -(2-bromoethoxy)- 7-fluoronaphthalene, 0 83 g (6 mmoles) of potassium carbonate and 50 ml of acetonitrile is heated under reflux for 7 hours After cooling, the reaction mixture is filtered, washed with acetonitrile, evaporated The crude product is recrystallized from ethanol Thus, 0 89 g (55 %) of the title product are obtained M p 104-107 °C Analysis for C₂₄H₂₂F₂N₂0₂ (408^'452) calculated C 70 58 %, H 5 43 % N 6 86 %, found C 70 48 % H 5 42 %, N 6 82 %

Example 41

1 -/4-(6-Fluorobenzo[d]ιsoxazole-3-yl)pιperιdιne-1 -yl/-3-(7- methoxynaphthalene-1 -yloxy)propane-2-ol hydrochloride

A solution of 0 55 g (2 5 mmoles) of 6-fluoro-3-(pιpeπdιne-4-yl)- benzo[d]ιsoxazole and 0 58 g (2 5 mmoles) of 2-(7-methoxy- naphthalene-1-yloxymethyl)oxιrane in 40 ml of ethanol is stirred at room temperature for 48 hours The reaction mixture is evaporated, and the residue is purified by chromatography on silica gel using a 19 1 mixture of chloroform and methanol as the eluent The oil obtained is dissolved in 100 ml of diethyl ether, and, to the solution, 4 ml of diethyl ether saturated with hydrogen chloride are added The crystals formed are filtered and dried Thus, 0 88 g (73 %) of the title product are obtained

M p 148-150 °C

Analysis for C₂₆H₂₈CIFN₂0₄ (486 98) calculated C 64 13 %, H 5 80 %, CI 7 28 %, N 5 75 % found C 63 87 %, H 5 89 %, CI 7 41 %, N 5 65 %

Example 42

6-Fluoro-3-[1 -/3-(7-methoxynaphthaiene-1 -yloxy)propyl/- pιperιdιne-4-yl]benzo[d]ιsoxazole

A mixture of 1 74 g (10 mmoles) of 7-methoxy-1 -naphthol 3 5 g (25 mmoles) of potassium carbonate and 10 ml of dimethylformamide is stirred at room temperature for 30 minutes then 3 11 g (12 mmoles) of 3-/1 -(3-chloropropyl)-pιpeπdιne-4-yl/-6- fluorobenzo[d]ιsoxazole are added to the reaction mixture heated under reflux for 10 minutes, then poured onto water The mixture is extracted with ethyl acetate, the organic phase is extracted several times with water and aqueous sodium hydroxide solution, then dried and evaporated The crude product is subjected to chromatography on silica gel using a 2 1 mixture of hexane and acetone as the eluent The base obtained is suspended in diisopropyl ether The crystals obtained is filtered, washed with diisopropyl ether, and dried.

Thus, 3.2 g (73.7 %) of the title product are obtained.

M.p.: 98-100 °C.

Analysis: for C₂₆H₂₇FN₂0₃ (434.52) calculated: C 71.87 %, H 6.26 %, N 6.45 %; found: C 71.61 %, H 6.35 %, N 6.40 %.

Example 43

6-Fluoro-3-[1 -/2-(7-methoxynaphthalene-1 -yloxy)ethyl/- pipehdine-4-yl]benzo[d]isoxazole hydrochloride

A mixture of 1.12 g (5 mmoles) of 6-fluoro-3-(pipehdine-4-yl)- benzo[d]isoxazole, 1.1 g (3.9 mmoles) of 1 -(2-bromoethoxy)-7- methoxynaphthalene, 1.08 g (7.8 mmoles) of potassium carbonate and 20 ml of acetonitrile is heated under reflux for 72 hours. The reaction mixture is cooled, filtered, and the mother liquor is evaporated. The evaporation residue is subjected to chromatography on silica gel using a 59:1 mixture of chloroform and methanol as the eluent. The substance obtained is dissolved in diethyl ether, and, to the solution, diethyl ether containing hydrogen chloride is added. The crystals precipitated are filtered, washed with ether, and dried. Thus, 1.6 g (90 %) of the title product are obtained. M.p.: 96-98 °C. Analysis: for C₂₅H₂₆CIFN₂0₃ (456.949) calculated: N 6.13 %, CI 7.78 %; found: N 6.09 %, CI 7.73 %.

Claims

Claims:

1. An alkylpipehdinylbenzo[d]isoxazoie derivative of the formula

wherein

X and Y mean, independently, a hydrogen atom, and simultaneously

R stands for a hydrogen atom, a halo atom, a Cι.₆ alkyl group or a Cι_-6 alkoxy group, and

X' and Y' represent, independently, a hydrogen atom, a halo atom, a Cι_-6 alkyl group or a Cι_-6 alkoxy group, or

X' forms together with Y' a 5- to 7-membered aromatic or partially saturated isocyclic or heterocyclic ring that can be fused with one or more further 5- to 7-membered aromatic or partially saturated isocyclic or heterocyclic ring, wherein each heterocyclic ring may contain, independently, one or more oxygen atom(s) and/or nitrogen atom(s) and/or sulfur atom(s) as the heteroatom, and each isocyclic or heterocyclic ring may be independently substituted by a halo atom, a Cι-_e alkyl group and/or a d-β alkoxy group, or b)

R, X' and Y' represent, independently, a hydrogen atom, and

X forms together with Y a 5- to 7-membered aromatic or partially saturated isocyclic or heterocyclic ring that can be fused with one or more further 5- to 7-membered aromatic, partially saturated or saturated, isocyclic or heterocyclic ring, wherein each heterocyclic ring may contain, independently, one or more oxygen atom(s) and/or nitrogen atom(s) and/or sulfur atom(s) as the heteroatom, and each isocyclic or heterocyclic ring may be independently substituted by a Cι_-6 alkyl group or a Cι_-6 alkoxy group, and a pharmaceutically suitable acid addition salt thereof.

2. An alkylpiperidinylbenzo[d]isoxazole derivative as claimed in Claim 1 , wherein

Z represents a hydrogen atom or a hydroxy group, R, X' and Y' mean, independently, a hydrogen atom, X forms together with Y a 5- to 6-membered aromatic or partially saturated isocyclic or heterocyclic ring, said latter ring containing one or more oxygen atom(s) and/or nitrogen atom(s) and/or sulfur atom(s) as the heteroatom, and the isocyclic or heterocyclic ring can be substituted by a Cι- alkyl group or a Cι- alkoxy group, n has a value of 0 or 1 , and a pharmaceutically suitable acid addition salt thereof.

3. An alkylpipehdinylbenzo[d]isoxazole derivative as claimed in Claim 2, wherein

Z represents a hydrogen atom or a hydroxy group, R, X' and Y' mean, independently, a hydrogen atom, X forms together with Y a benzene ring or a 5-membered aromatic or partially saturated heterocyclic ring containing two oxygen atoms or two nitrogen atoms and a sulfur atom as the heteroatom, n has a value of 0 or 1 , and a pharmaceutically suitable acid addition salt thereof.

4. An alkylpiperidinylbenzo[d]isoxazole derivative of the formula

as claimed in Claim 1 , wherein Z represents a hydrogen atom or a hydroxy group, R stands for a hydrogen atom,

X' and Y' mean, independently, a hydrogen atom or a Cι- alkoxy group, or X' forms together with Y' a 5- to 6-membered aromatic or partially saturated isocyclic or heterocyclic ring, said latter ring containing two oxygen atoms or a nitrogen atom as the heteroatom, and the isocyclic or heterocyclic ring is optionally fused with a benzene ring, n has a value of 0 or 1 , and a pharmaceutically suitable acid addition salt thereof

5 An alkytpιperιdιπylbenzo[d]ιsoxazole derivative as claimed in Claim 4, wherein

Z represents a hydrogen atom or a hydroxy group,

R stands for a hydrogen atom,

X' and Y mean, independently, a hydrogen atom or a methoxy group, or X' forms together with Y a benzene ring or pyrrol ring which latter is fused with a benzene ring, n has a value of 0 or 1 , and a pharmaceutically suitable acid addition salt thereof

6 A process for the preparation of an alkylpiperidmylbenzo- [d]ιsoxazole derivative of the formula I, wherein Z, R, X, Y, X', Y' and n are as defined in Claim 1 , or a pharmaceutically suitable acid addition salt thereof, characterized in that

a) a pιperιdιnylbenzo[d]ιsoxazole derivative of the formula

wherein X, Y, X', Y and R are as defined in connection with formula I, or

b) a compound of the formula

wherein Q represents a leaving group, Z' stands for a hydrogen atom or a hydroxy group or Q forms together with Z' an oxygen atom, X, Y, X', Y, R and n are as defined in connection with formula I, is reacted with 6-fluoro-3-(pιpeπdιne-4-yl)benzo[d]- isoxazole, and, if desired, an obtained alkylpιpeπdιnylbenzo[d]ιsoxazole derivative of the formula I is converted to a pharmaceutically suitable acid addition salt or the base is liberated from the salt

7 A pharmaceutical composition comprising an alkyl- pιperιdιnylbenzo[d]ιsoxazole derivative of the formula I, wherein Z, R X, Y, X', Y' and n are as defined in Claim 1 or a pharmaceutically suitable acid addition salt thereof as the active ingredient and one or more conventional carπer(s)

8 A pharmaceutical composition as claimed in Claim 7 comprising an alkylpιperιdιnylbenzo[d]ιsoxazole derivative of the formula I, wherein Z, R, X, Y, X', Y' and n are as defined in Claim 2, or a pharmaceutically suitable acid addition salt thereof as the active ingredient

9 A pharmaceutical composition as claimed in Claim 8 comprising an alkylpιperιdιnylbenzo[d]ιsoxazole derivative of the formula I, wherein Z, R, X, Y, X', Y' and n are as defined in Claim 3, or a pharmaceutically suitable acid addition salt thereof as the active ingredient

10 A pharmaceutical composition as claimed in Claim 7 comprising an alkylpιperιdιnylbenzo[d]ιsoxazole derivative of the formula la, wherein Z, R, X', Y' and n are as defined in Claim 4, or a pharmaceutically suitable acid addition salt thereof as the active ingredient

11 A pharmaceutical composition as claimed in Claim 10 comprising an alkylpιperιdιnylbenzo[d]ιsoxazole derivative of the formula la, wherein Z, R, X', Y' and n are as defined in Claim 5, or a pharmaceutically suitable acid addition salt thereof as the active ingredient

12 A method of treatment in which a patient suffering from especially a disease of the central nervous system is treated with a non-toxic dose of an alkylpιperιdιnylbenzo[d]ιsoxazole derivative of the formula I, wherein Z, R, X, Y, X', Y' and n are as defined in Claim 1 , or a pharmaceutically suitable acid addition salt thereof

13 The use of an alkylpιpeπdιnylbenzo[d]ιsoxazole derivative of the formula I, wherein Z, R, X, Y, X', Y' and n are as defined in Claim 1 , or a pharmaceutically suitable acid addition salt thereof for the preparation of a pharmaceutical composition having psychotropic effect