NO153726B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 4- (NAPHTHALENYLOXY) PIPERIDE INGREDIATES. - Google Patents

Description

The present invention relates to an analogue

procedure for the preparation of therapeutically active 4-(naphthalenyloxy)piperidines which are useful as neuroleptics

tical tranquilizers whose use does not induce significant

significant extrapyramidal side effects.

1-phenyl-cj-(1-piperidyl)alkanones constitute an important

class of central nervous system depressants. Various compounds of this class are, for example, described in US patent documents 3,438,991, 3,518,276, 3,576,810, 3,816,433,

3,888,867 and 3,907,812. Although compounds of this type have often been found to have potent antipsychotic activity, their use has been limited due to the appearance of serious

equal extrapyramidal side effects and transient hypotension.

It has now been found that the new co-(4-naphthalenyloxy-l-piperidyl)-1-phenylalkanones exhibit strong antipsychotic activity without causing significant extrapyramidal side effects and with little effect on blood pressure.

The invention thus relates to an analog method

for the preparation of therapeutically active compounds of the formula,

wherein is a halogen atom or a pharmaceutically acceptable acid addition salt thereof.

Preferred compounds of formula I are: 4-[4-(1-naphthalenyloxy)-1-piperidyl]-1-(4-fluorophenyl)-1-

butanone and

4-[4-(2-naphthalenyloxy)-1-piperidyl]-1-(4-fluorophenyl)-1-butanone.

The pharmaceutically acceptable acid addition salts of compounds of formula I/ are also active as antipsychotic agents. Suitable salts include those with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, carboxylic acid such as acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid , dihydroxy-maleic acid, benzoic acid, phenylacetic acid, 4-aminobenzoic acid, 4-hydroxybenzoic acid, anthranilic acid, cinnamic acid, salicylic acid, aminosalicylic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid and mandelic acids, and sulfonic acids such as methanesulfonic acid, 2-hydroxyethanesulfonic acid and p-toluenesulfonic acids.

New intermediates for the preparation of compounds of formula I are compounds of formula II

The novel compounds of formula I are antipsychotic agents useful when administered alone or in the form of pharmaceutical preparations containing the novel compounds in combination with a pharmaceutical carrier as neuroleptic sedatives in warm-blooded animals. Neuroleptic sedatives are useful for treating patients who exhibit symptoms of psychosis, such as schizophrenia, or severe anxiety, agitation or aggressiveness. Such agents have a calming effect on a psychomotor activity, including a state of general rest for a patient without inducing sleep. Patients suitable for treatment with antipsychotic preparations containing compounds of formula I include warm-blooded animals such as birds, for example turkeys and chickens, and mammals, for example mice, rats, dogs, cats, horses, pigs, cattle, sheep and people.

Pharmaceutical preparations containing compounds of formula I can be in solid or liquid form, such as

tablets, capsules, powders, solutions, suspensions or emulsions, and can be administered orally, parenterally, intraperitoneally, intramuscularly or subcutaneously, or topically, for example transdermally or transmucosally. The amount comprising an effective amount of the new compound provided in a unit dose, and the nature and amount of the pharmaceutical carrier will vary widely according to the nature of the pharmaceutical composition and the body weight of the patient to be treated. The treatment of a patient in need of sedation will amount to from 0.002 to 100 mg/kg body weight per day to achieve the desired calming effect. For a human patient, this degree of sedation can be achieved by means of an antipsychotic preparation in the form of tablets containing from 0.2 to 200 mg of active ingredient and a suitable pharmaceutical carrier taken from 1 to 4 times daily. Small unit doses will be required to achieve a comparable neurolytic effect in smaller animal species.

The compounds of general formula I together with suitable pharmaceutical carriers can be in the form of solid unit dosage forms such as tablets, capsules and powders, in the form of suppositories or anchored in a polymeric matrix. When producing solid unit dosage forms, it may be desirable to micronize the compound to be used. In solid unit dosage forms, the compounds can be combined with conventional carriers, e.g. binders such as acacis, corn starch or gelatin, solubilizers such as corn starch, guar gum or alginic acid, lubricants such as stearic acid or magnesium stearate and inert fillers such as lactose, sucrose or corn starch.

The compounds of general formula I may also be administered as liquid suspensions or solutions using a sterile liquid such as an oil, water, an alcohol or mixtures thereof, with or without the addition of a pharmaceutically acceptable surfactant, suspending agent or emulsifying agent, for oral, topical or parenteral administration.

For liquid preparations, the compounds of formula I can be suitably formulated with oils, e.g. bound oils such as peanut oil, sesame oil and olive oil, fatty acids such as oleic acid and isostearic acid, and fatty acid esters such as isopropyl myristate and fatty acid glycerides, with alcohols such as ethanol, isopropanol and propylene glycol, with water or with mixtures thereof.

Peanut oil and sesame oil are particularly useful in the preparation of formulations for intramuscular injection. Oils can also be used in the production of soft gelatin-type formulations and suppositories. Water, physiological salt water, aqueous dextrose and related sugar solutions and glycerols such as polyethylene glycol can be used in the preparation of liquid formulations which can appropriately contain suspending agents such as pectin, carbomers, methylcellulose, hydroxypropylcellulose or carboxymethylcellulose, as well as buffers and preservatives.

When 4-[4-(2-naphthalenyloxy)-1-piperidyl]-1-(4-fluorophenyl)-1-butanone hydrochloride was administered intraperitoneally to mice at a dose of 0.06 mg/kg, the overall toxicity of d -amphetamine inhibited in 50% of the tested mice according to the procedure described by J. Burn et al., Arch. Int. Pharmacodyn, 113, 290-295 (1955), thus showing an antipsychotic efficacy, whereas a dosage level of 0.98 mg/kg of the known sedative chlorpromazine is required to achieve a similar degree of response. The compounds according to the invention exhibit neuroleptic activity by inhibiting pernicious self-grooming in mice tested according to the method described by A. Kandel et al., Fed. Proe, 19 (1. Pt. 1), 24 (1060).

A neuroleptic potency of these compounds is accompanied by a reduced tendency to induce extrapyramidal side effects in patients treated with a neuroleptic effective dose compared to known antipsychotic agents. As an indication of the reduced extrapyramidal effect of the compounds according to the invention, it can be stated that when 4-[4-(2-naphthalenyloxy)-1-piperidyl]-1-(4-fluorophenyl)-1-butanone hydrochloride was administered intraperitoneally to mice, a dose of 34.0 mg/kg was required to antagonize the behavioral effects of apomorphine in 50% of the mice tested following the general method described by P. A. J. Janssen et al., in Arzneim-Forsch. 10, 1003 (1060), whereas only 1.4 mg/kg chlorpromazine was required to achieve a similar effect.

Comparison tests between compounds produced according to the present application and compounds known from US patent specification 3,243,645 and Norwegian patent specification 135,248 have been carried out. No comparison has been made with compounds known from US Patent 4,134,982. These compounds are not available for testing, and they are further structurally significantly different from the present compounds. Although the compounds known from US patent document 3,260,723 are also structurally different from the present one, there is incomplete data for one of the compounds described in this patent document, and this data has been included in the following test report.

The following tests illustrate the antipsychotic activity and possible extrapyramidal side effects for the following compounds:

4-[4-(2-naphthalenyloxy)-1-piperidyl]-1-(4-fluoro-phenyl)-1-butanone hydrochloride (compound according to ex. 1 ) MDL No. 18,203A 4-[4-( 1-naphthalenyloxy)-1-piperidyl]-1-(4-fluorophenyl)-1-butanone hydrochloride (compound according to example 2)

MDL No. 18,478A

and the following known compounds:

Known connections

Norwegian patent document 135 248

US Patent 3,743,645 US Patent 3,260 7 20

Reference connections

Test A

Antagonism of D-amphetamine-induced lethality in 1-matched mice

Groups of 15 male Swiss mice obtained from Laboratory Supply were housed in disposable plastic mouse cages (approximate dimensions: 29 x 18 x 13 cm) which were partially filled with a layer of sawdust. Mesh lids were used to keep the animals in the cages. Free access to food and water was allowed. Room temperature during the experiment was maintained as close as possible to 22.3°C.

The animals were treated with the test compound, and at selected times the animals were then treated with d-amphetamine sulfate, 9.0 mg/kg i.p., prepared as a solution in distilled water so that 10 ml/kg provided the required dose. The number of animals that were alive in each group was counted approx.

18 hours after the administration of amphetamine.

The dose of the test compound which provided protection against amphetamine-induced lethality in 50% of the test mice (ED^) was calculated with a computer program for analyzing the data.

A dose of 9.0 mg/kg d-amphetamine sulfate i.p. resulting in an 80-100% mortality in the control groups. Antipsychotic agents are specific inhibitors of this effect and exhibit activity at doses far below those that elicit any obvious effect in mice.

Attempt B

Inhibition of apomorphy-induced stereotypy in rats

Male rats weighing between 100 and 300 g, obtained from Laboratory Supply - Sprague-Dawley rats, were individually housed in cages with 12.70 mm galvanized steel mesh in 5 linearly arranged 15.24 x 15.24 x 15.24 cm cells. Each cell was fitted with a snap lid.

All drugs and vehicle controls were injected at doses contained in a standard volume of 1.0 ml/kg. The standard agonist, apomorphine hydrochloride, was prepared as a solution in distilled water containing 0.1% ascorbic acid to retard oxidation. The test compound was prepared as a solution or was maintained as a suspension with Tween® 80 in distilled water. Injections of the test compounds were made intraperitoneally; the apomorphine hydrochloride was injected subcutaneously.

The rats were injected with a selected dose of the test compound followed at a suitable interval by 1.0 mg/kg apomorphine hydrochloride and returned to their cells. Observations for apomorphine stereotypy were initiated 15 min after the apomorphine challenge and continued for a period of 3 min. Responses recorded and graded for degree and frequency/persistence included sniffing, licking or chewing, rearing on hind legs and seeking. Incessant, excessive sniffing with the nose through a hole in the cage fabric separates them from normal inspection behaviour. Chewing and licking activity occurs without any obvious motivation. A rearing up on the hind legs and searching, i.e. the animals stand on their hind legs, the head is bent backwards and the nose is pushed into the cloth hole, is not normally observed other than occasionally in an untreated rat. A rearing of the hind legs without reaching is an incomplete reaction that was rarely observed and not recorded.

In determining the mean dose of a selected compound in terms of inhibition of apomorphine (ED^), graded doses were administered to groups of rats, and the number of rats showing significant inhibition of apomorphine was recorded for each group.

The EDj-Q values were obtained with a calculator programmed for Berkson analysis of the dose-effect data. Inhibition of this behavior has previously been associated with clinical antipsychotic activity, but has now been found to reflect the extrapyramidal propensity of a test compound rather than a beneficial antipsychotic effect.

The magnitude of the ratio between the effective dose of a test compound in the apomorphine antagonism model and the effective dose in the amphetamine antagonism model is expressed as a measure of the test compound's suitability as an antipsychotic agent free of extrapyramidal side effects. The different behavior of known antipsychotics is consistent with this separation of effects: the well-known neuroleptic haloperidol, which is known to produce clear signs of extrapyramidal side effects at antipsychotic doses, antagonizes apomorphine at a low dose relative to that dose which is effective in the amphetamine antagonism model, while the well-known neuroleptic thioridazine ("Mellaril"), which exhibits very weak evidence of extrapyramidal activity at antipsychotic doses, is effective in the apomorphine antagonism model only at a dose much higher than its effective dose in the amphetamine antagonism model.

The effective doses in the amphetamine antagonism test and the apomorphine antagonism test and the ratios between the effective dose in the apomorphine antagonism test and the effective dose in the amphetamine antagonism test were obtained for the test compounds MDL 18.203A, MDL 18.478A, the indicated known compounds, and for the reference compounds haloperidol and thioridazine .

For MDL 18.19 2A, 4-(4-fluorophenoxy)-piperidine, and for the compound according to US patent 3,260,723, only results from the amphetamine antagonism test are available.

The largest administered dose of the 1-naphthyloxy compound, MDL 18,478A, and the 2-naphthyloxy compound,

MDL 18.203A, i.e. 200 mg/kg and 80 mg/kg, were insufficient to antagonize the effect of the standard dose of apomorphine in the tested animals. The ratios of these toxic effects to the effective dose in the amphetamine antagonism test are therefore minimum values that are lower than the ratios that would have been obtained using the real EDgQ values.

These test results show that MDL 18.203A and

MDL 18,478A, i.e., the present naphthyloxy-substituted compounds, are superior as neuroleptic sedative agents to the phenoxy-substituted compounds known from US Patent 3,743,645 and US Patent 3,260,723, and the hydroxybenzyl-substituted compounds known from Norwegian patent document 135 248.

This superiority is reflected by their greater antipsychotic activity as demonstrated by an ED^q-

value for the 2-naphthyloxy compound of only 0.06 mg/kg and 0.6 mg/kg for the 1-naphthyloxy compound in the antiamphetamine test, against 10 mg/kg for MDL 18.192, i.e. the phenoxy compound without the butyrophenone substituent. The superiority of the present compounds is also shown by their lower ability to induce extrapyramidal side effects expressed in absolute terms as shown by an ED^ value in terms of apomorphine antagonism of from 6.2 to 37.7 for the known phenoxy and hydroxybenzyl compounds, while a dose of 80 mg/kg for the 2-naphthyloxy compound or 200 mg/kg for the 1-naphthyloxy compound was insufficient to inhibit apomorphine-induced stereotypy in any of the mice tested. The reduced ability to induce extrapyramidal side effects expressed relatively, is also shown by the ratio between the ED5Q values for the two tests of over 1300 for the 2-naphthyloxy compound and over 330 for the 1-naphthyloxy compound, but only 33.5

for the known compound which exhibits the greatest separation of these effects, namely MDL 11,881.

On the basis of these tests, it is clear that the present naphthyloxy compounds are more active as antipsychotic agents than the known compounds, while these will not cause neuromotor side effects that have traditionally accompanied treatment with conventional antipsychotic agents.

The analogy method according to the invention is characterized in that

a) a compound of formula

or an acid addition salt thereof, is alkylated with a compound of formula

wherein halo is Cl, Br or 1, in a suitable solvent in the presence of a base and optionally in the presence of a catalytic amount of potassium iodide for from 24 to 96 hours at a temperature of from 20 to 180°C, and

b) when a pharmaceutically acceptable salt is desired, that the compound thus obtained is reacted with a pharmaceutical

acceptable acid.

Compounds of formula II are prepared by dealkylation or debenzylation of compounds of formula IIb

wherein R 3 is lower alkyl or phenyl(lower alkyl). Compounds of formula IIb are prepared by reacting an N-substituted-4-piperidinol salt of formula V in which R 3 is lower alkyl or phenyl (lower alkyl) and M<+> is an alkali metal cation, such as potassium, sodium or lithium, with a naphthalene fluoride of formula VI to form a 1-(lower alkyl) or 1-phenyl(lower alkyl)-4-naphthalenyloxypiperidine of formula IIb. The compounds of formula II are prepared by dealkylation of the N-substituted compounds of formula IIb using a chloroformic acid ester of formula wherein R 4 is 2,2,2-trichloroethyl, vinyl, substituted vinyl, benzyl, substituted benzyl or cycloalkyl, which is reacted with a compound of formula IIb in the presence of a deprotonating agent, forming a 1-(R 2 -oxycarbonyl)-4-(naphthalenyloxy)piperidine of formula VII where R and 1 R 2 have the meanings given above, after which the R 2 -oxycarbonyl group is removed by means of a mild reducing agent, such as zinc dust in acetic acid or methanol, or by acid hydrolysis, as illustrated in the following:

Naphthalene fluorides of formula VI are well known and can be prepared by well-known methods, e.g. by the methods described by W. Adcock et al., in J.Am.Chem. Soc. 89(2), 386-390 (1967) and in J. Am. Chem. Soc. 98(7), 1701-1711

(1976).

Piperidinol salts of formula V are prepared by reacting the corresponding 1-lower alkyl- or 1-phenyl-(lower alkyl)-4-piperidinol with a strong base such as an alkali metal hydride, an alkali metal amide or alkyllithium according to generally known procedures. The piperidinol salt is reacted with the naphthalene fluoride of formula VI in the presence of a polar, aprotic solvent at a temperature of from 50 to 200 u C or at the boiling temperature of the solvent for from 1 to 24 hours. Suitable solvents included tetrahydrofuran, dimethoxyethane, diglyme, dioxane, hexamethylphosphoric triamide, dimethylacetamide, dimethylsulfoxide, 1-methyl-2-pyrrolidone, sulfolane and especially dimethylformamide.

The reaction is stopped and the resulting N-substituted compound of formula IIb or its acid addition salt is isolated by conventional methods, for example the reaction mixture can be filtered and the solvent removed, the product isolated which is then purified by recrystallization and dried. Suitable solvents for recrystallization are, for example, lower aliphatic alcohols such as methanol, ethanol and isopropanol, ketones such as acetone and butanone, esters such as ethyl acetate, hydrocarbons such as hexane, and combinations thereof.

The 1-lower alkyl- or 1-phenyl(lower alkyl)-4-(naphthalenyloxy)piperidine of formula IIb thus prepared is then reacted with an ester of chloroformic acid in the presence of an aprotic solvent, and preferably an acid scavenger to form a carbamate of formula VII, which then cleaves to form the corresponding 1-unsubstituted-4-(naphthalenyloxy)piperidine of formula IIa. Suitable chloroformate esters are those which provide R 1 -oxycarbonyl substituents which can be cleaved from the nitrogen atom of the compound of formula VII hydrolytically or under reducing conditions under which the naphthalene ring is not hydrogenated. Such chloroformate esters include 2,2,2-trichloroethyl esters, which can be cleaved by reduction with zinc dust or by electrolysis, the benzyl ester, benzyl esters substituted with phenyl, methoxy, methyl, phenyl-azo, cyano, bromine or chlorine, vinyl esters and cycloalkyl esters, such as cyclohexyl , cyclopentyl, adamantyl and isobornyl esters, which can be split by acid hydrolysis using strong acids such as hydrochloric or hydrobromic acids, or using mild acids such as trifluoroacetic acid in suitable solvents. Chloroformate esters suitable for displacing alkyl and benzyl substituents from tertiary amines, and methods suitable for cleaving the various R 1 -oxy-carbonyl groups from the nitrogen atoms, are described by M. Bodanszky et al., in Peptidesynthesis, 2nd Edition (John Wieley & Sons), pp. 21-37 (1976), and R. Olofson et al. in US Patent 3,905,981. The preferred chloroformate ester for the dealkylation of compounds of formula II wherein R 2 is lower alkyl or phenyl (lower alkyl) is 2,2,2-trichloroethyl chloroformate.

Suitable solvents for the reaction of an N-substituted compound of formula IIb with a chloroformate ester are aprotic organic solvents, e.g. ethers, such as diethyl ether and tetrahydrofuran, aromatic hydrocarbons such as toluene and benzene, chlorinated hydrocarbons such as chloroform, dichloroethane and methylene chloride, or mixtures thereof. The preferred solvent is methylene chloride. The reaction may be carried out in the presence of a small amount, for example 1-5% by weight of the amount of compound of formula IIb, of a proton scavenger, which may be an inorganic base such as sodium or potassium carbonate, a strong organic base such as triethylamine or a mixture thereof. The reaction mixture is maintained at a temperature between 0° C. and the reflux temperature of the solvent for from 1 to 96 hours. The thus obtained 1-(R4-oxycarbonyl)-4-(naphthalenyloxy)-piperidine of formula VII is isolated, for example, by extraction in an organic solvent and evaporation of the solvent according to generally known procedures, and the R4-oxycarbonyl group is split by an appropriate method.

In a preferred embodiment

an N-lower alkyl- or N-phenyl (lower alkyl)-substituted compound of formula Ilb is boiled under reflux in methylene chloride with a slight excess, for example from 1.01 to 1.3 equivalents, preferably 1.1 equivalents, of 2,2,2-trichloroethyl chloroformate in the presence of a trace amount of a proton scavenger for from 6 to 24 hours at a temperature of from 15 to 40° C., preferably at room temperature. The product is extracted in ether, washed with dilute acid and concentrated in vacuo. The resulting 1-(2,2,2-trichloro-ethoxycarbonyl)-4-(naphthalenyloxy)piperidine is dissolved in a solvent selected from acetic acid, aqueous acetic acid, a lower alkanol such as methanol, an aqueous lower alkanol, and preferably a mixture of acetic acid, water and an ether, such as tetrahydrofuran. At a temperature of from 0 to 50° C, preferably at room temperature, from 1 to 5 equivalents, preferably approx. 2 equivalents, zinc dust with stirring, and the reaction is allowed to proceed for from 1 to 6 hours until gas evolution ceases. The solvents are evaporated and the N-unsubstituted compound of formula II is separated from the rest of the zinc salts by basic

making, extraction in an organic solvent, washing to remove water-soluble solutes, conversion to a water-soluble acid addition salt, washing with organic solvents to remove neutral organic contaminants and rebasing. The N-unsubstituted compound is recrystallized according to known methods, preferably in the form of an acid addition salt from suitable solvents, such as lower aliphatic alcohols, ketones, esters and combinations thereof.

Free bases of formula II prepared by the above-mentioned method can be converted into acid addition salts by reaction with a suitable acid according to well-known methods.

The compounds of formula I are prepared by reacting a piperidine derivative of formula II with a small excess of a u)-haloalkylphenyl ketone of structure VIII

in the presence of an excess of an acid acceptor such as, for example, sodium bicarbonate, potassium bicarbonate, sodium carbonate or potassium carbonate, and optionally a small amount of potassium iodide, in a suitable solvent. If desired, two or more equivalents of the piperidine derivative of formula II

in relation to the compounds of formula VIII, an inorganic acid acceptor is used instead. The compounds of formula I

can also be prepared from acid addition salts of the compound of formula II by reacting the acid addition salt with a compound of structure VIII in the presence of at least two equivalents of the inorganic basic acid acceptor. The reaction mixture can be reacted over a wide temperature range. In general, a reaction temperature of from 20 to 180° C. is used. The reaction is carried out over a period of from 1 to 4 days, during which period any water formed can be collected.

As examples of suitable solvents for this reaction

can be mentioned toluene, xylene, chlorobenzene, methylisobutyl ketone and lower aliphatic alcohols such as ethanol, propanol and butanol.

After the reaction has ended, the product is isolated according to known methods, for example the reaction mixture can be filtered and the solvent removed, and the product isolated. Alternatively, the filtrate can be treated with an ethereal solution of a suitable inorganic or organic acid to give the corresponding salt of the product. The crude product is filtered off, purified by recrystallization and dried. Suitable solvents for recrystallization are, for example, lower aliphatic alcohols such as methanol, ethanol and isopropanol, ketones such as acetone and butanone, nitriles such as acetonitrile and combinations thereof.

The general method for the preparation of the compounds of formula I can be illustrated by the following reaction core:

wherein is as above and halo is a reactive halogen such as bromine, chlorine or iodine.

Compounds of formula VIII are commercially available or can be prepared by methods well known in the art. Compounds of formula VIII

can e.g. is prepared by reacting the suitable w-halo-alkanoyl halide and a (substituted)benzene in the presence of a Lewis acid, such as aluminum chloride, or by reacting a (4-substituted) phenyl-Grignard reagent with a suitable co-haloalkylnitrile .

Compounds of formula I prepared in the form of free bases can be converted into their acid addition salts by reaction with a pharmaceutically acceptable acid.

The following preparations 1-4 illustrate the preparation of starting materials, while the following examples illustrate the invention.

Production 1

4-(2-naphthalenyloxy)-1-(phenylmethyl)piperidine hydrochloride

A solution of a solution of

4.75 g (25.0 mmol) of 1-phenylmethyl-4-piperidinol in 20 mL of dry dimethylformamide followed by a solution of 3.83 g (26.2 mmol, 1.05 equivalents) of 2-fluoronaphthalene in 20 mL of dimethylformamide. The mixture was heated to 75° C. for 23 hours, cooled, poured into ice water and extracted twice with ether. The extracts were washed with water and physiological saline, dried over magnesium sulfate and filtered. The filtrate was treated with HCl/methanol and the resulting 4-(2-naphthalenyloxy)-1-(phenylmethyl)piperidine hydrochloride was recrystallized from butanone/methanol. Sm.p. 24 2 - 244° C. Preparation 2

4-(1-naphthalenyloxy)-1-phenylmethylpiperidine hydrochloride

When, in the method according to preparation 1, 1-fluoronaphthalene is used instead of 2-fluoronaphthalene, 4-(1-naphthalenyloxy)-1-(phenylmethyl)piperidine hydrochloride is obtained with m.p. 222 - 224° C.

Manufacturing 3

4-(2-naphthalenyloxy) piperidine hydrochloride

To a stirred solution of 64.6 g (0.204 mol) 4-(2-naphthalenyloxy)-1-phenylmethylpiperidine in 500 ml methylene chloride was added 37.0 ml (0.268 mol) 2, 2 , 2-trichloroethyl-chloroformate and about. 200 mg potassium carbonate. The mixture was stirred at room temperature for 48 hours and poured into a small volume of ether and water. The organic phase was washed with dilute hydrochloric acid and aqueous potassium carbonate, dried over magnesium sulfate and concentrated in vacuo.

The resulting 1-(2,2,2-trichloroethoxycarbonyl)-4-(2-naphthalenyloxy)piperidine was dissolved in a mixture of 250 ml of acetic acid, 250 ml of tetrahydrofuran and 125 ml of water.

28.5 g (0.436 mol) of zinc dust was added in portions with stirring and the exothermic reaction was allowed to proceed for 2 1/2 hours. The mixture was filtered and the solvents removed in vacuo. The residue was partitioned between ether and aqueous sodium hydroxide,

and the organic phase.was washed with water and extracted with dilute aqueous hydrochloric acid. The acid extracts were washed with ether, basified with sodium hydroxide, and extracted into ether and toluene, and the organic solution was washed, dried over magnesium sulfate, and concentrated in vacuo to give 4-(2-naphthalenyloxy)piperidine, which was redissolved in ethanol. /ether and treated with dry HCl, and the hydrochloride salt was recrystallized from butanone/methanol. Melting point: 229.5 - 231.5° C.

Manufacturing 4

4-(1-naphthalenyloxy) piperidine hydrochloride

When in the method according to preparation 3 4-(1-naphthalenyloxy)-1-phenylmethyl)piperidine was used instead of 4-(2-naphthalenyloxy)-1-phenylmethyl)piperidine, 4-(1-naphthalenyloxy)piperidine was obtained -hydrochloride.

Example 1

4-[ 4-( 2- naphthalenyloxy)- 1- piperidyl]- 1-( 4- fluorophenyl)- 1- butanone hydrochloride

A solution of 5.67 g (25 mmol) 4-(2-naphthalenyloxy)-piperidine, (27.4 mmol) 4-chloro-1-(4-fluorophenyl)-1-butanone,

0.1 g of potassium iodide and 4.5 g of potassium bicarbonate in 100 ml of toluene were heated for 48 hours with stirring on a steam bath. The mixture was partitioned between 100 ml portions of methylene chloride/ether and water, and the organic phase was dried over MgSO 4 . A solution of an excess of HCl in ether was added and the resulting precipitate was recrystallized from methanol/butanone to give 5-[4-(2-naphthalenyloxy)-1-piperidyl]-1-(4-fluorophenyl)-1 -butanone hydrochloride.

Sm.p. 219 - 221.5°C.

Example 2

4-[ 4-( 1- naphthalenyloxy)- 1- piperidyl]- 1-( 4- fluorophenyl)- 1- butanone hydrochloride

When in the method according to example 1 4-chloro-1-(4-fluorophenyl)-1-butanone and 4-(1-naphthalenyloxy)piperidine hydrochloride were used instead of 4-(2-naphthalenyloxy)piperidine hydrochloride, 4-[4-(1-naphthalenyloxy)-1-piperidyl]-1-(4-fluorophenyl)-1-butanone hydrochloride was obtained with m.p. 220 - 222.5°C.

Claims (3)

1. Analogy method for the preparation of therapeutically active compounds of formula wherein R is a halogen atom or a pharmaceutically acceptable acid addition salt thereof, characterized in that a) a compound of formula or an acid addition salt thereof, is alkylated with a compound of formula wherein halo is Cl, Br or I, in a suitable solvent in the presence of a base and optionally in the presence of a catalytic amount of potassium iodide for from 24 to 96 hours at a temperature of from 20 to 180°C, and b) when a pharmaceutical acceptable salt, it is desired that the compound thus obtained be reacted with a pharmaceutically acceptable acid. 2. Process according to claim 1, in the preparation of 4-[4-(2-naphthalenyloxy)-1-piperidyl]-1-(4-fluorophenyl)-1-butanone or a pharmaceutically acceptable acid addition salt thereof, characterized in that 4-( 2-naphthalenyloxy)-piperidine is alkylated with 4-chloro-1-(4-fluoro-phenyl)-1-butahone. 3. Process according to claim 1, in the preparation of 4-[4-(1-naphthalenyloxy)-1-piperidyl]-1-(4-fluorophenyl)-1-butanone or a pharmaceutically acceptable acid addition salt thereof, characterized in that 4-( 1-naphthalenyloxy)-piperidine is alkylated with 4-chloro-1-(4-fluoro-phenyl)-1-butanone.