The present invention relates to new 1,4-disubstituted piperidine derivatives having the general formula (I) :

(I)

wherein X is hydroxymethylene or methoxymethylene, Y is a 3- membered methylene sequence and R is a p-fluorophenyl group, as well as their pharmaceutically acceptable addition salts.

The compounds of the present invention are obtained according to Scheme I. In effect, the al ylation of 4- (p-fluorobenzoyl) 0 piperidine with the halogen derivative Cl-Y-O-R, wherein Y and R are as previously defined, in the presence of an alkali and a non polar solvent, leads to 4- (p-fluorobenzoyl) -1- (3-p- fluorophenoxy)propylpiperidine (II). Subsequent reduction of this intermediate with sodium borohydride yields the final compound of formula (I, X: CHOH, Y: (CH ₂ ) ₃ , R: p-F-C ₆ H ₄ ) . In contrast, the compound of formula (I, X: CH(OCH ₃ ), Y: (CH ₂ ) ₃ , R: p-F-C ₆ H ₄ ) requires first the protection of 4- (p-fluoro¬ benzoyl)piperidine. For this purpose, this compound is conveniently reacted with di-tert-butyl dicarbonate in an organic basic medium. N-tert-butoxycarbonyl derivative (III)

Scheme 1

(I, X: CH(OCH ₃ ), Y: (CH ₂ ) ₃ , R: p-F-C ₅ H ₄ )

Abbreviations: t-Bu-O-CO-O-CO-O-t-Bu: O/ ^' -fwr-butyl dicarbonate

Et,N: Triethylaminβ

EtOH: Ethanol

THF: Tetrahydrofuran

is then formed, which enables to be handled safe from dialkylation in subsequent synthesis steps. The reduction of N-tert-butoxycarbonyl derivative with sodium borohydride in ethanol provides the corresponding secondary alcohol (IV) . Its methylation with iodomethane in the presence of a strong base in an ether-like solvent leads to the methoxy-derivative (V) . The strong base and the choice ether-like solvent are sodium hydride and tetrahydrofuran respectively. The following step is the unprotected reaction of (V) in acid medium. This reaction occurs conveniently by dissolving hydrogen chloride in a mixture of water and ethanol. The piperidinyl-derivative (VI) is then susceptible to be alkylated under analogous conditions to those employed for the obtention of (II) . Thus, the final compound of the formula (I, X: CH(OH ₃ ), Y: (CH ₂ ) ₃ , R: p-F-C ₆ H ₄ ) is obtained.

US Patent No. 4588728 describes the treatment of psychosis with cis-9- [3- (3,5-dimethyl-piperazinyl) ropyl]carbazole. US Patent No. 4709094 describes the preparation of 1,3- disubstituted guanidines as well as their utility in the diagnosis and treatment of hallucinations associated with psychotic disorders and chronic mental depression. US Patent

No. 4929734 describes the preparation of N-substituted 1-

(1,2,3,6-tetrahydro-3-piridinyl)oximes and N-substituted 1- (l,2,3,6-tetrahydro-4-piridinyl)oximes and their use in treating depression, psychosis and/or inflammatory diseases. US Patent No. 5061728 describes the use of 4-phenyl-l,2,3,4- tetrahydro-l-naphthalenamine derivatives in treating

psychosis and inflammation and their use as immunosupressants. US Patent No. 5086054 describes the preparation of arylcycloalkylpolyalkyl-amines and their use as antipsychotic, anti-ische ic, anti-apoplectic, anti- dementia agents and anticonvulsants. US Patent No. 5162341 describes the use of various compounds for combating amphetamine and analogous drug abuse. US Patent No. 5175174 describes the preparation of N-phenyl-piperidyl-4-a ine derivatives and their use as Class III antiarryhthmic agents, potassium channel blockers, antipsychotics, anticonvulsants and neuroprotectors. US Patent No. 5158947 describes the preparation of N-piperidyl-alkyl-benzazepine derivatives and their utility for the treatment of psychoneurosis. US Patent No. 5116995 describes the preparation of 4- (aminoalkyl) - carbazole and their use as antipsychotics. US Patent No. 5149817 describes the preparation of 4-phenyl- and 4-thienyl- tetrahydropyridine and their use for treating depression, mania, schizophrenia and cerebral ischemia. US Patent No. 5109002 discloses 1-cyclo-alkyl-piperidine derivatives and their use as antipsychotics and for treating dyskinesia.

The compounds disclosed in all these patents share their affinity as ligands for sigma ( σ) receptors of Nervous System. To this regard, literature reviews by B.L. Largent et al ("Eur. J. Pharmacol.", 151, 345-7, 1988), S.I. Deutsch et al ("Clinical Neuropharmacology", 11(2), 105-119, 1988) and T.P. Su ("Eur. J. Biochem.", 200. 633-642, 1991) are illustrative of the biochemical, pharmacological and clinical

aspects of sigma-receptor ligands.

Applicants have found out that although the compounds of the present invention are chemically very different from those of the above prior art patents, they show a high affinity as ligands for sigma receptors. Due to such an activity, they are potentially useful in the treatment of some sigma receptor-related mental disorders, mainly psychosis and schizophrenia.

Moreover, and from a chemical viewpoint, the closest compound to the compounds of this invention is 4- (p-fluorobenzoyl) -1- (3-p-fluorophenoxy)propylpiperidine (II), which is described in US Patent No. 3576810 (1971) . In accordance with this patent, the compounds generically disclosed therein are claimed to be useful as tranquilizers, and as such, they show antianxiety activity. Obviously, no indication of a possible effect on sigma-receptors is given in this patent, insomuch as this term was introduced later on. However, applicants have found out that 4- (p-fluorobenzoyl) -1- (3-p-fluoro- phenoxy)propylpiperidine (II) is effectively bound to sigma- receptors, but also bound to D ₂ receptors to a great extent. In contrast, the compounds of the present invention show as a major advantage over the compound of the formula (II) their high selectivity on sigma receptors versus D ₂ receptors, which results in a lesser possibility of developing extrapyramidal effects on account of the interaction with D ₂ receptors (Table 1) . Furthermore, the lower incidence of

side-effects in the compounds of this invention with regard to the compound of the formula (II) has been made evident by means of the stereotypy inhibition test (Table 2) and Irwin test (Table 3) .

Specific binding to σ and D ₂ receptors has been tested as follows:

a receptors: A 2-nM solution of radioactive 3-PPP ((+) [ ³ H] 3- [3-hydroxyphenyl] -N- (1-propyl) -piperidine) , which acts as a specific ligand, was incubated with the membrane corresponding to 40 mg of guinea-pig total brain for 90 min at 25°C buffered at pH 8.5 with Tris.HCl. Thus, total binding of ligand to membranes was attained. Non-specific binding was then determined by adding a micromolar concentration of unlabelled 3-PPP. IC _J0 values (inhibitory concentration 50%) were calculated from the inhibition rate of the specific binding obtained by adding eleven different concentrations of the compounds to be tested. After the incubation was completed, the samples were filtered through a glass fiber filter and then washed three times with Tris.HCl buffer. The amount of receptor-bound radioactivity was retained on the membrane and determined by liquid scintillation counting.

D-, receptors: A 2-nM solution of radioactive spiperone ( [ ³ H]spiperone) , which acts as a specific ligand, was incubated with the membrane corresponding to 20 mg of rat striatum for 20 min at 35°C buffered at pH 7.4 with Tris.HCl.

The non-specific binding was then determined by addition of a micromolar concentration of unlabelled spiperone. IC _J0 (inhibitory concentration 50%) was calculated from the inhibition rate of the specific binding obtained by addition of eleven different concentrations of the compounds to be tested. After the incubation was completed, the sample was filtered through a glass fiber filter and then washed three times with Tris.HCl buffer. The amount of receptor-bound radioactivity was retained on the membrane and determined by liquid scintillation counting.

Stereotypy inhibition test: Male Sprague-Dawley rats, weighing 200-300 g were used. The animals were weighed and then placed in individual transparent boxes. At time 0 the compounds to be tested were administered intraperitoneally. 0.25% agar was used as vehicle. After 30 min, apomorphine was injected subcutaneously at a dose of 1.5 mg/kg in a concentration of 0.6 mg/ l. At 40, 50, 60, 90 and 120 min, stereotypy was scored from (-) to (+++) according to the following criteria: (-) absence of stereotypy or any abnormal movement; (+) presence of slight stereotyped movements of the head and intermittent sniffing; (++) intense movements of the head, mild licking interspersed with sniffing; and (+++) intense licking and/or gnawing. Results are expressed as ED ₅₀ in mg/kg for a better quantification.

Irwin test: It consists in a package of tests intended to find out the properties of a compound as well as the

magnitude of such properties which are completely unknown.

Assessment begins with general observations until reaching gradually more detailed observations. Changes are arbitrarily scored from the observations of control animals. On the basis of animals' behaviour, the following parameters were assessed:

a) General examination: sex, weight, age, ... b) Behavioural examination: alertness, locomotor activity, mood. c) Neurological examination: central nervous system excitation, autonomic nervous system study, body carriage, motor incoordination, muscular tone, reflexes and general signs.

The results have been expressed as the first dose causing behavioural and neurological undesirable effects. Under the experimental conditions described, IC _S0 values on σ and D ₂ receptors expressed in nanomolar concentrations (nM) are shown in Table 1. This table also contains the D ₂ /σ ratio of selectivity and the D ₂ /σ ratio of relative selectivity to compound (II) (Compound II, Example 6, D ₂ /σ = 1) . Preferred compounds are those whose D ₂ /σ ratio of selectivity is higher. Compound (II) , Ex. 6, is less selective.

Table 1

Compound IC ₅₀ (nM) Selectivity Relative selectivity σ D ₂ D ₂ / σ D ₂ /σ

II , Ex . 6 60 . 9 155 2 . 5 1

Ex . 5 75 .2 631 8 . 4 3 . 4

Ex. 7 9 . 44 1430 151 . 5 60 . 6

In Table 2, the results on stereotypy, expressed as ED ₅₀

(mg/Kg) , show that the ED ₅₀ of the compounds of the present application was higher than that for reference compound (II) .

This indicates that the compounds of the invention are less potent as inductors of undesirable abnormal movements attributed to D ₂ receptors. This finding is, in addition, consistent with the biochemical results shown in Table 1.

Moreover, the results of Irwin test (Table 3) show that no undesirable effects were observed for the compounds of the invention until doses were several times higher than those for reference compound (II) . Furthermore, among the side effects of the compounds of the invention, unlike reference compound (II) , neither decreased muscular tone nor catalepsy were found.

Table 2

Compound ED ₅₀ (mg/Kg)

Tabla 3

Compound First dose (mg/kg) Side effects

II, Ex. 6 10 Inhibition of motor activity, motor inc oordinat i on , hypothermia, decreased muscular tone and catalepsy

Ex. 100 Inhibition of motor activity, motor incoordination and hypothermia

Ex. 40 Inhibition of motor activity, motor incoordination and hypothermia

The experimental results obtained suggest that the compounds of the invention can be useful in the treatment of sigma receptor-related nervous system diseases, and especially in anoxia, anxiety, convulsions, dyskinesia, drug addiction, schizophrenia, hypoxia, cerebral ischemia, mania, psychosis and stress. The compounds can be administered in combination with suitable vehicles via the oral, rectal or parenteral routes. These compounds are administered in doses ranging from 0.5 up to 100 mg per day, more preferably from 1 up to 30 mg per day.

EXAMPLE 1; 1- (tert-butoxycarbonyl) -4- (p-fluorobenzoyl) piperidine

A mixture of 4- (p-fluorobenzoyl)piperidine (10 g, 48 mmole) , di-tert-butyl dicarbonate (10.5 g, 48 mmole) and tri- ethylamine (10 mL) in 50 mL of tetrahydrofuran was stirred at room temperature for 16 hours. The solvent was evaporated in vacuo and the residue was dissolved in benzene. The solution thus obtained was poured into water and ice, acidified with hydrochloric acid, stirred for 10 min and decanted. The benzene extract was washed with two further portions of water, dried over anhydrous sodium sulfate and evaporated in vacuo. There were obtained 12 g (83 %) of 1- (tert-butoxy- carbonyl) -4- (p-fluorobenzoyl)piperidine in the form of a colourless oil that solidifies slowly. NMR (CDC1 ₃ ) : 1.47 (s, 9 H) ; 1.6-1.8 (m, 2 H) ; 1.8-1.9 (m, 2 H) ; 2.9 (ta, 2 H) ; 3.4 (t t, 1 H) ; 4.2 (da, 2 H) ; 7.15 (t, 2 H) ; 7.98 (d d, 2 H) .

EXAMPLE 2; 1- (tert-butoxycarbonyl) -4- (1- (p-fluorophenyl) -1- hydroxy ethyl)piperidine

To a solution of l- ( ert-butoxycarbonyl) -4- (p- fluorobenzoyl)piperidine (10 g, 33 mmole) in ethanol (100 mL) , 2 g of sodium borohydride were added. After stirring for 2 h at room temperature, the solution was evaporated in vacuo, the residue was dissolved in benzene, poured into water and ice, and then added hydrochloric acid to provide pH 5-6. The organic extract was dried over anhydrous sodium sulfate and evaporated to give 5.9 g (59 %) of 1- (tert- butoxycarbonyl) -4- (1- (p-fluorophenyl) -1-hydroxymethyl) piperidine. NMR (CDC1 ₃ ) : 1.0-1.2 (m, 1 H) ; 1.2-1.3 (m, 2 H) ; 1.43 (s, 9 H) ; 1.6-1.8 (m, 1 H) ; 1.9-2.0 (da, 1 H) ; 2.5-2.7 (m, 2 H) ; 4.0-4.2 (m, 2 H) ; 4.36 (d, 1 H) ; 7.02 (t, 2 H) ; 7.26 (d d, 2 H) .

EXAMPLE 3 ; 1- ( tert-butoxycarbonyl) -4 - (1- (p- fluorophenyl) -1- methoxymethyl) iperidine

0.8 g of sodium hydride (dispersion in 80% paraffin), previously washed with hexane, were suspended in 25 mL of anhydrous tetrahydrofuran. To the suspension, a solution of 1- (tert-butoxycarbonyl) -4- (1- (p-fluorophenyl) -1- hydroxymehyl)piperidine (5 g, 16 mmole) in 25 mL of tetrahydrofuran was added. The mixture was stirred for 30 min at room temperature and then 2 mL of iodomethane were added. After further stirring for 16 h, the mixture was

evaporated in vacuo and the residue was dissolved in chloroform. The solution was poured into water and ice and neutralized by addition of hydrochloric acid. The chloroform extract was dried over anydrous sodium sulfate and evaporated to give 5 g of 1- (tert-butoxycarbonyl) -4- (1- (p-fluorophenyl) -

1-methoxymethyl)piperidine in the form of an oil which can be employed without further purification. NMR (CDC1 ₃ ) : 1.0-1.3

(m, 3 H) ; 1.44 (s, 9 H) ; 1.6-1.8 (m, 1 H) ; 2.0 (da, 1 H) ;

2.5-2.7 (m, 2 H) ; 3.16 (s, 3 H) ; 4.78 (d, 1 H) ; 4.0-4.2 (m, 2 H) ; 7.03 (t, 2 H) ; 7.20 (d d, 2 H) .

EXAMPLE 4; 4- (1- (p-fluorophenyl) -1-methoxymethyl)piperidine

To a solution of 1- (tert-butoxycarbonyl) -4- (1- (p- fluorophenyl) -1-methoxymethyl)piperidine (5 g, 15 mmole) in 35 mL of ethanol, 35 mL de HC14 M solution were added. After stirring for 1 h at room temperature, the mixture was concen¬ trated in vacuo until removal of ethanol, and the resulting aqueous solution was washed with benzene and added to NaOH to provide pH 14. The aqueous solution was next extracted with chloroform three times, and the chloroform extracts were dried over sodium sulfate and evaporated to give 2.4 g (69 %) of 4- (1- (p-fluorophenyl) -l-methoxymethyl) piperidine in the form of an oil which solidifies slowly. Melting point: 73- 76°C. IR ( Br, cm ^-1 ) : 3270,1610,1510, 1230, 1090. NMR (CDC1 ₃ ) : 1.0-1.3 (m, 3 H) ; 1.6-1.7 (m, 1 H) ; 2.0 (da, 1 H) ; 2.2 (sa, 1 H) ; 2.4-2.6 (m, 2 H) ; 3.0 (da, 1 H) ; 3.12 (da, 1 H) ; 3.16 (s, 3 H) ; 3.78 (d, 1 H) ; 7.02 (t, 2 H) ; 7.20 (dd, 2 H) .

EXAMPLE 5; 4- (1- (p-fluorophenyl) -1-methoxy)methyl-l- (3-p- fluorophenoxy)propylpiperidine hydrochloride

To a solution of 4- (1- (p-fluorophenyl) -1-methoxymethyl) piperidine (2.2 g, 10 mmole) and 3- (p-fluorophenoxy)propyl chloride (1.9 g, 10 mmole) in 40 mL of acetonitrile, 1.5 g of anhydrous potassium carbonate and 0.2 g of potassium iodide were added. After heating under reflux overnight, the mixture was allowed to cool and evaporated to dryness. The residue was added to water and extracted with ethyl ether. The ethereal extracts were dried over sodium sulfate and evaporated. The oil thus obtained was dissolved in acetone- ether (1:7) and precipitated by addition of an ethereal solution of HC1 to give 2 g of 4- (1- (p-fluorophenyl) -1- methoxy) methyl-1- (3-p-fluorophenoxy) propylpiperidine hydrochloride. Melting point: 109-111°C. Elemental analysis calculated for C ₇₂ 1 ₂₁ F ₂ N0 ₂ . UC1 : C, 64.15; H, 6.85; N, 3.40; Cl 8.61; Found: C, 64.10; H, 6.67; N, 3.56; Cl, 8.60. IR (KBr, cm" ¹ ): 3200-3700, 2300-2900, 1510, 1230. NMR (CDC13) : 1.3 (da, 1H) ; 1.8 (m, 1H) ; 2.0 (m, 1 H) , 2.2 (m, 1 H) ; 2.4- 2.8 (m, 6 H) ; 3.1-3.2 (s + m, 5 H) ; 3.5 (d, 1 H) ; 3.7 (d, 1 H) ; 3.8 (d, 1 H) ; 4.1 (m, 2 H) ; 6.9-7,0 ( , 4 H) ; 7.15 (t, 2 H) ; 7.4 (dd, 2 H) .

EXAMPLE 6: 4- (p-fluorobenzoyl) -1- (3-p-fluorophenoxy)propyl piperidine hydrochloride

Amixture of 4- (p-fluorobenzoyl)piperidine hydrochloride

(8.8 g; 36 mmole), 3- (p-fluorophenoxy)propyl chloride (7 g,

36 mmole) , anhydrous potassium carbonate (10 g, 71 mmole) and potassium iodide (0.5 g) in 75 mL of acetonitrile were heated under reflux for 16 h. The reaction mixture was allowed to cool, filtered and evaporated to dryness. To the residue thus obtained, 150 mL of water were added, and then extracted with

3 portions of 100 mL of ethyl ether. The ethereal extracts were evaporated to dryness, the product was redissolved in isopropanol (50 mL) y precipitated by addition of a solution of HC1 in isopropanol. The product was filtered and dried in vacuo to give 6 g of 4- (p-fluorobenzoyl) -1- (3-p- fluorophenoxy)propylpiperidine hydrochloride. Melting point: 190-192°C. Elemental analysis calculated for : C, 63.71; H, 6.11; N, 3.54; Cl, 8.96. Found: C, 63.72; H, 6.10; N, 3.62; Cl, 8.91. IR (KBr, cm ^"1 ): 3300-3700, 2400-2800, 1690, 1600, 1510, 1230. NMR (dβ-D SO) : 2.0 (m, 4 H) ; 2.2 (m, 2 H) ; 3.15 (m, 2 H) ; 3.20 ( , 2 H) ; 3.6 (da, 2 H) ; 3.75 (m, 1 H) ; 4.05 (t, 2 H);6.98 (m, 2 H) ; 7.14 (t, 2 H) ; 7.4 (t, 2 H) ; 8.15 (dd, 2 H) .

EXAMPLE 71 4- (1- (p-fluorophenyl) -1-hydroxy) ethyl-1- (3-p- fluorophenoxy)propylpiperidine

To a solution of 4- (p-fluorobenzoil) -1- (3-p- fluorophenoxy)propylpiperidine hydrochloride (10 g, 25 mmole) in ethanol (150 mL) , 6 g of NaBH4 were added and then stirred at room temperature for 2 hours. The solvent was evaporated in vacuo, water was added and the product was extracted with

ethyl acetate. The extracts were dried over Na2S04 and evaporated to give 7 g of 4- (1- (p-fluorophenyl) -1-hydroxy) methyl-1- (3-p-fluorophenoxy)propylpiperidine in the form of an oil which solidifies slowly. Elemental analysis calculated for C ₂₁ H _2j F ₂ N0 ₂ : C, 69.79; H, 7.25; N, 3.88. Found: C, 69.57; H,

7.17; N, 4.04. IR (KBr, cm ^"1 ) : 3000-3200, 1510, 1220. RMN

(CD30D) : 1.22 (m, 2 H) ; 1.4 (m, 1 H) ; 1.6 (m, 1 H) ; 1.8-2.0 m, 4 H); 2.5 (m, 2 H) ; 2.9 (da, 1 H) , 3.02 (da, 1 H) , 3.94

(t, 2H) ; 4.35 (d, 1 H) ; 6.8-7.1 (m, 6 H) ; 7.38 (dd, 2 H) .