CA1123440A

CA1123440A - 4-(naphthalenyloxy)piperidine derivatives

Info

Publication number: CA1123440A
Application number: CA355,369A
Authority: CA
Inventors: Albert A. Carr; Robert A. Farr
Original assignee: Merrell Dow Pharmaceuticals Inc
Current assignee: Aventis Pharmaceuticals Inc
Priority date: 1979-08-06
Filing date: 1980-07-03
Publication date: 1982-05-11
Also published as: AU534398B2; DE3028064C2; NZ194248A; JPS5626875A; IT1146966B; FR2463129A1; DK150477B; NO153726B; DK150477C; NL8004147A; BE884581A; FR2463129B1; DE3028064A1; DK337280A; ES493591A0; IL60593A0; GB2056447A; SE448728B; IT8049394A0; SE8005493L

Abstract

4-(NAPHTHALENYLOXY)PIPERIDINE DERIVATIVES
ABSTRACT OF THE DISCLOSURE
Novel compounds of the formula wherein n is an integer of from 2 to 5, R is hydrogen, alkyl, alkoxy, halogen or trifluoromethyl, R1 is hydrogen, alkyl, alkoxy or halogen, and Z is carbonyl or hydroxy-methylene and their pharmaceutically acceptable acid addition salts are useful as antipsychotic agents having a low potential for extrapyramidal side effects. The novel compounds are prepared from novel intermediates of formula

Description

~I~Z3~

~-(NAPHTHALENYLOXY)?IPERIDINE DERIVATIVES
FIELD OF THE INVENTION
This invention relates ro novel derivatives of 4-(naphthalenyloxy)piperidines and methods for their pre-paration. ~lore particularly it relates to new 4-naphthal-enyloxypiperidines, useful as chemical intermediates, and their N-(~-benzoylalkyl) and N-~W-hydroxy-~-phenylalkyl3 derivatives, useful as neuroleptic tranquilizers ~hose use does not induce slgnificant extrapyramidal side effects.
DESCRIPTION OF THE PR IOR ART
1-Phenyl-w-(1-piperidyl)alkanones constitute an im~or-tant class of central nervous system depressants. Various compounds of this class are claimed, -for example, in U.S.
pa.ents 3,438,991; ~,518~-76; ~,~76,810; 3,816,~2~;
3~8~8,867 and ~,907,812. Although compounds of -thi, type are often found to have potent anripsycho-cic activityJ their use has been limited by the occurrence of serious extra-pyramidal side efrects and transient hypotension.
It has now been discovered tha~ the novel w-!~-naphthalenyloxy-1-piperidyl)-1-phenylalkanones and the corresponding naphthalenyloxy-r~-phenyl-1-pip2ridinalkanois of this invention display potent antipsycho~ic ac~ivi~y without inducin~ significant extrapyramidal side e,fects and with li~tle ef-fect on blood pressure.
SUMMAR',' OF TrlE I~I~ENTION
Novel compounds of rormula ! . . . : ' ~ , . ; , . . : ' ~` ~Ll ~ 8 M-10~1 R ~
O Formula I

(cH2)n-z~Rl wherein n is an integer Gf from 2 to 5; R is hydrogen, alkylJ alkoxy, halogen or trifluormethyl; R1 is hydrogen, alkyl, alkoxy or halogen; and Z is carbonyl or hydroxy-5 methylene, are useful as antipsychotic agents. These anti-psychotic compounds may be prepared from inter-mediates of Formula II

R ~

Formula Il wherein R2 is hydrogen, lower alkyl or phenyl(lower alkyl) and R has the meaning defined above. Compounds oF For-mula II are also novel compounds and are included in this invention. Included in the invention are the pharmaceu-tically acceptable acid addition salts of compounds of Formulas I and II and individual optical isom~rs of the compounds of Formula I.
DETA!LED DESCRIPTION OF THE INVENTION
Compounds of Formula I include w-~4-(1- and 2-naph-thalenyloxy-1-piperidyl)~ (4-substituted)phenyl-1-alkanones of Formula III

~ z34,~ M-1031 R ~
I Formula III
O
(CH 2 ) n-C ~ R1 and 4-(1- and ~-naphthalenyloxy)-~-(4-substituted)phenyl-1-piperidinealkanols of Formula IV

R ~

Formula IV
N OH
(cH2)n-cH-~)-Rl wherein n, R and R1 have the meanings defined above, their individual Opticâl isomers, and their pharmaceuti-cally acceptable acid addition salts.
As used herein, alkyl is taken to mean straight or branched chain alkyl groups having from 1 to 4 carbon atoms. Illustrative examples of alkyl groups are methyl, ethyl, propyl and tertiary butyl. Lo~ler alkyl is taken to mean straight chain alkyl of from 1 to 3 carbon atoms.
Alkoxy is taken to mean straight or branched chain alkoxy groups having from 1 to 4 carbon atoms. illustrative 1~ examples of alkoxy groups are methoxy, ethoxy and isopro-poxy. Halogen is taken to mean fluorine, chlorine or bromine.
The substituent R may be located in any posi-tion oF
the naphthalene ring system other than the position occu-?ied by the (4-piperidyloxy) substituent.
Preferred embodiments of this invention are compounds of Formula I ~herein Z is carbonyl; also preferred are embodiments of this invention wherein n is equal to 3.

~: - . - : . . .
, -- : - . . ~ : : ,. :: :: :, . :
.

3~ M-1031 Further preferred embodiments of this invention are com-pounds of Formula I wherein R is selected from hydrogen and halogen. Preferred embodiments of this invention also include compounds of Formula I wherein R1 is halogen and especially fluorine.
Exemplary compounds of Formula I are:
4-[4-(1-naphthalenyloxy)-1-pipleridyl]-1-(4-fluorophenyl) 1-butanone, 4-[4-(2-naphthalenyloxy)-1-piperidyl]-1-(4-fluorophenyl)-1-butanone, 4-[4-(6-chloro-2-naphthalenyloxy)-1-piperidyl]-1-(4-fluoro-phenyl)-1-butanone, 3-[4-(5-methoxy-1-naphthalenyloxy)-1-piperidyl]-1-(4-chlorophenyl)-1-propanone, 4-[4-(2-naphthalenyloxy)-1-piperidyl]-1-(4-methylphenyl)-1-butanone, 5-[4-(1-methyl-2-naphthalenyloxy)-1-piperidyl]-1-(4-ethoxy-phenyl)-1-pentanone, 4-[4-(8-methoxy-2-naphthalenyloxy)-1-piperidyl]-1-phenyl-1-butanone, 6-[4-(5-fluoro-1-naphthalenyloxy)-1-piperidyl]-1-(4-fluoro-phenyl)-1-hexanone, 4-~4-(2-trifluoromethyl-1-naphthalenyloxy)-1-piperidinyl]-1-(4-bromophenyl)-1-butanone, 4-(1-naphthalenyloxy)-~-(4-f7uorophenyl)-1-piperidir,e-butanol) 4-(2-naphthalenyloxy)-a-(4-fluorophenyl)-1-piperidine-butanol, 4-(4-trifluoromethyl-2-naphthalenyloxy)-~-phenyl-1-piperi-dinebutanol, 4-(o-bromo-2-naphthalenyloxy)-a-~4-bromophenyl)-1-ptperi-dinepropanol, 4-(7-isopropyl-1-naphthalenyloxy)-a-(4-fluorophenyl)-1-piperidinepentar,ol, 4-(3-ethoxy-2-naphthalenyloxy)-a-(4-methoxyphenyl)-1-piperidinebutanol, ,,, ~. , . ,. .
, - , .
: . . -. ~. , . :, .. . . -ç . . . .

- - . ~ - , ~ ~ z 3 ~ ~ M-1031 4-(2-naphthalenyloxy-~-(4-ethylphenyl)-1-piperidine-hexanol, 4-(8-fluoro-1-naphthalenyloxy)-~-(4-fluorophenyl)-1-piperidinebutanol, and 4-(2-methyl-1-naphthalenyloxy)-c-(phenyl)-1-piperidine-butanol.
The invention also includes the pharmaceutically acceptable acid addition salts of compounds of Formula 1, which are also active as antipsychotics. Suitable salts include those of inorganic acids, such as hydrochloric, hydrobromic, sulfuric and phosphoric acids; carboxylic acids, such as acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, dihydroxymaleic, benzoic, phenylacetic, 4-aminobenzoic, 4-hydroxybenzoic, anthranilic, cinnamic~ salicylic, aminosalicylic, 2-phenoxybenzoic, 2-acetox~ybenzoic and mandelic acids; and sulfonic acids, such as methanesulfonic, 2-hydroxy-ethanesulfonic and p-toluenesulfonic acids.
Novel intermediates for the preparation of compounds of Formula I are compounds of Formula ll R ~

~N) wherein R has the meaning defined above, and R2 is hydro-gen, lower alkyl or phenyl(lower alkyl) and acid addition salts thereof. Preferred embodiments of Formula ll are compounds wherein R2 is hydrogen, methyl or phenylmethyl and those wherein R is hydrogen or halogen.
Exemplary compounds of Formula ll include:
4-(~-naphthalenyloxy)piperidine, 4-(2-naphthalenyloxy)piperidine, 4-(6-chloro--2-naphthalenyloxy)piper~dine, ~.,.
... . .

- , - : ~ - :: : - : , :

- :~lZ3~ ~ M-1031 :

4-(5-methoxy-1-naphthalenyloxy)piperidine, 4-(1-methyl-2-naphthalenyloxy)piperidine, 4-(8-methoxy-2-naphthalenyloxy)piperidine, 4-(5-fluoro-1-naphthalenyloxy)piperidine, 4-(2-trifluoromethyl-1-naphthalenyloxy)piperidine~
4-(6-bromo-2-naphthalenyloxy)piperidine, 4-(7-isopropyl-1-naphthalenyloxy)piperidine, 4-(4-trifluoromethyl-2-naphthalenyloxy)piper;dine, 4-(3-ethoxy-2-naphthalenyloxy~piperidine, 4-(8-fluoro-1-naphthalenyloxy)piperidine, 4-(2-methyl-1-naphthalenyloxy)piperidine 1-methyl-4-(1-naphthalenyloxy)piperidine, 1-methyl-4-(6-chloro-2-naphthalenyloxy)piperidine, 1-methyl-~-(1-methyl-2-naphthalenyloxy)piperidine, 1-methyl-4-(~-trifluoromethyl-2-naphthalenyloxy)piperidine, 1-ethyl-4-(5-fluoro-1-naphthalenyloxy)piperidine, 1-methyl-4-(7-isopropyl-1-naphthalenyloxy)piperidine, 1-propyl-4-(8-methoxy-2-naphthalenyloxy)piperidine, 1-(phenylmethyl)-4-(2-naphthalenyloxy)piperidine, 1-(2-phenylethyl)-4-(5-methoxy-l-naphthalenyloxy)piper dine, 1-(phenylmethyl)-4-(2-trifluoromethyl-1-naphthalenyloxy)-piperidine, 1-(phenylmethyl)-4-(6-bromo-2-naphthalenyloxy)piperidine, ;

2~ 1-(pnenylmethyl)-4-(3-ethoxy-2-naphthalenyloxy)piperidi~ne, 1-(3-phenylpropyl)-4-(8-fluoro-1-naphthalenyloxy)piperi-dine, and their acid addition salts.
The novel compounds of Formula I are antipsychotic agents useful when administered alone or in the form of pharmaceutical preparations contalning the novel compounds in combination ~ith a pharmaceutical carrier as neuro-leptic tranquilizers in warm blooded animals. Neuroleptic tranquil7zers are useful for treatment of patients showing symptoms of psychoses, such as schizophrenia, or of severe anxiety, agitation or aggressiveness. Such agents have a tranquilizing effect on psychomotor activity, induc-ing a state of general quiescence in the patient without inducing sleep. Patients suitable for treatment with

3 4 ~O

antipsychotic compositions containing compounds of Formula i inc1ude warm blooded animals such as birds, for example turkeys and chickens, and mammals, for example mice, rats, dogs, cats, horses, pi95, cattle, sheep and humans.
Pharmaceutical compositions containing compounds of Formula I may be in solid or liquid form, such as tablets, capsules, powders, solutions, suspensions or emulsions, and may be administered orally, parenterally, for example, intraperitoneally, intramuscularly or sub-cutaneously, or topically, for example, transdermally or transmucosally. The quantity comprising an effective amount of the novel compound provided in a unit dosage and the nature and quantity of the pharmaceutical carrier will vary widely according to the type of pharmaceutical composition and the body weight of members of the patient population to be treated. The treatment of a patient in need of tranquilizing will provide from 0.002 to 100 mg/kg of body weight of the patient per day to achieve the desired tranquilizing effect. For a human pattent this degree of tranquilization may be achieved by means of an antipsychotic composition in the form of tablets con-taining from 0.2 to 200 mg of the active compound and an appropriate pharmaceutical carrier taken from 1 to 4 times a day. Small unit dosages will be required to 2~ achieve a comparable neuroleptic effect in smaller species of animals.
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 a suppository, or embedded in a polymeric matrix. In the preparation of solid unit dosage forms it may be desirable to micronize the compound to be employed. In solid unit dosage forms the compounds can be combined with conventional carriers, for example, binders~ such as acacia, corn starch or gelatin; disinte-grating agents, such as corn starch. guar gum or alginic acid; lubricants, such as stearic acid or magnesium .. . . ., . ~ ;

: '.`: `

~- 10~1 3~a~0 stearate: and inert fillers, such as lactose, sucrose or corn starch.
The compounds of general Formula I may also be ad-ministered as liquid suspensions or solutions using a sterile liquid, such as an oil, water, an alcohol or mix-tures thereof, with or without the addition of a pharmaceu-tically suitable surfactant, suspending agent, or emulsify-ing agent, for oral, topical or paren-teral aclministration.
For liquid preparations, the compounds of Formula I
can be formulated suitably with oils, for example, fixed 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 gl~cerides; with alcohols, such as ethanol, isopropanol and propylene glycol; with water; or with mixtures thereof.
Peanut oil and sesame oil are particularly useful in preparation of formulations for intramuscular injection.
Oils can also be employed in the preparation of formula-tions of the soft gelatin type and suppositories. Water,saline, aqueous dextrose and related sugar solutions and glycerols, such as polyethyleneglycol, may be employed in the preparation of liquid formulations which may suit-ably contain suspending agents, such as pectin, carbomers, methyl cellulose, hydroxypropyl cellulose or carboxy-methyl celluloseJ as well as buffers and preservatives.
Illustratively, when 4-r4-(2-naphthalenyloxy)-1-piperidyl]-1-(4-fluorophenyl)-1-butanone hydrochloride was administered intraperitoneally to mice at a dosage of o.o6 mg/kg the aggregate toxicity o-F d-amphetamine was inhibited in 50~ of the mice tested according to the procedures disclosed by J. Burn et al., Arch. Int.
Pharmacodyn. 113~ 290-5 !1955), thus demonstrating anti-psychotic effectiveness, whereas a dosage level of o.g8 ~5 mg/kg of the known tranquilizer chlorprom~zine is required to attain a similar level of response. Similarly, com-pounds of this invention evince neuroleptic activity ~ ' M-1031 ~lZ3~`~0 through the inhibition of pernicious preening in mice tested according to the method disclosed by A. Kandel et al., Fed. Proc., 19 (1, Pt. 1), 24 (1960).
The neuroleptic potency of these compounds is accom-panied by a reduced tendency to produce extrapyramidalside effects in patients treated wiih a neuroleptically effective dosage as compared with known antipsychotic agents. Indicative of the reduced extrapyramidal effect of the compounds of this invention, when 4-[4-(2-naphtha-lenyloxyj-1-piperidyl~-1-(4-fluorophenyl)-1-butanone hydro-chloride was administered intraperitoneally to mice, a dosage of 34.0 mg/kg was required to counteract the behavioral effects of apomorphine in 50~ of the mice tested according to the general method disclosed by P. A. J. Janssen et al.~ in Arzneim-Forsch. 10, 1003 (1960), whereas only 1.~ mg/kg of chlorpromazine was required to attain a similar effect.
Compounds of Formula I are prepared by alkylation of intermediate compounds of Formula IIa, o I Formula IIa H

which represent compounds of Formula II wherein R2 is hydrogen and R has the above-identified meaning. Com-pounds of Formula IIa are themselves prepared by dealkyla-tion or debenzylation of compounds of Formula IIb, R ~

~ Formula IIb N

- l . , . . .. ~ .... . . . .. . ..

M-~0~1 ll'h34~0 -9a-wherein R3 is lower alkyl or phenyl(lower alkyl) and R
has the above-defined meaning, which represent compounds of Formula ll wherein R2 is lower alkyl or phenyl(lower alkyl). It is thus apparent that all of the compounds of Formula ll are useful intermediates for the pharmaceu-tically useful compounds of Formula 1. Compounds of Formula ll are also new and represent a part of this invention.
Compounds of Formula llb are prepared by reaction of an N-substituted-4-piperidinol salt of Formula V

O-M+
Formula V
R3 .
wherein R3 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 Vl -R ~ F Formula Vl :

,:

,~ ,.

;..

`: : i . . !, ` . `; . ` ., . M-1031 Z3~ ~

wherein R has the meaning defined above, to produce a 1-(low2r alkyl) or 1-phenyl(lower alkyl)-4-naphthalenyloxy-piperidine of Formula llb. The compounds of Formula lla, wherein R2 is hydrogen, are prepared by dealkylation o~
N-substituted compouncis of Formuia llb by means of a chloro-formic acid ester of Formula R40C-C1, wherein R4 is 2,2,2-trichloroethyl, vinyl, substituted vinyl, benzyl, substi-tuted benzyl or cycloalkyl, which is reacted with the com-pound of Formula llb in the presence of a proton scavenger, to produce a 1-(R4-oxycarbonyl)-4-(naphthanlenyloxy)piper-idine of Formula Vll R
O
Formula Vil IN
O=C-O-R4 :~
wherein R and R4 have the meanings defined above, and removal of the R4-oxycarbonyl groùp by means of a mild 15 reducing agent, such as zinc dust in acetic acid or ;
methanol, or by acid hydrolysis, as illustrated by the following:

O M+ R ~ R
F > O ~:
N
R3 V Vl llb N ~ :
R3 :

R ~ reduction R ~ ~ R~OCCl < hydrolysis lla ~ Vll H O=C-OR4 M -10~ 1 Naphthalene fluorides of Formula Vl are well known and may be prepared by methods well known in the art, -For example 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).
Piperidtnol salts of Formula V are prepared by react-ing 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 alkyl lithium according to generally known procedures. The piperidinol salt is reacted with the naphthalene fluoride -~
of Formula Vl in the presence of a polar, aprotic solvent at a temperature of from about 50 to about 200C or at the boiling temperature of the solvent for from about 1 to about 24 hours. Suitable solvents include tetrahydrofuran, dimethoxyethane, diglyme, dioxane, hexamethylphosphorus triamide, dimethylacetamide, dimethylsulfoxide, 1-methyl-2-pyrrolidone, sulfolane and, especially~dimethyl formamide.
The reaction is quenched and the resulting N-substitu-ted compound of Formula llb or its acid addition salt isisolated by conventional means, for example, the reaction mixture may be filtered and the solvent removed, isolating the product, which is purified by recrystallization and dried. Suitable solvents for recrystallization are, for exam?le, lower aliphatic alcohols, such as methanol, ethanol and isopropanoli ketones, such as acetone and but-anone; esters, such as ethyl acetate; hydrocarbons, such as ` hexane; and combinations thereof.
The thus prepared 1-lower alkyl- or 1-phenyl(lower-alkyl)-4-(naphthalenyloxy)piperjdine of Formula llb 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 Vll, which is subsequently cleaved to yield the corresponding 1-unsubstituted-4-(naph-thalenyloxy)piperidine oL Formula lla. Suitable chloro-formic acid esters are those which yield R4-oxycarbonyl . ~ . .

M -10:~ 1 ~lZ3~40 substituents which may be cleaved from the nitrogen atom of the compound of Formula Vll hydrolytically or by reduc-ing conditions under which the naphthalene ring is not hydrogenated. Such chloroformic acid esters include the 2,2,2-trichloroethyl ester, which may be cleaved by reduc-tion with zinc dust or by electrolysis; the benzyl ester, benzyl esters subst7tuted by phenyl, methoxy, methyl, phenylazo, cyano, bromo or chloro, vinyl esters, and cyclo-alkyl esters, such as the cyctohexyl, cyclopentyl, ada-mantyl and isobornyl esters, which may be cleaved by acidhydrolysis by means of strong acids, such as hydrochloric or hydrobromic acids, or by means of mild acids~ such as trifluoroacetic acid, in suitable solvents. Chloroformic acid esters suitable for displacing alkyl and benzyl sub-stituents from tertiary amines and methods suitable for the cleavage of the various R4-oxycarbonyl groups from the nitrogen atoms are described by M. Bodanszky et al., in Peptide Synthesis, 2nd Edition ~ohn Wiley & Sons) p. 21-37 (1976) and by R. Olofson et al. in U.S. patent 3,905,981, which are hereby incorporated by reference.
The preferred chloroformic acid ester for the dealkylation of compounds of Formula il wherein R2 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 llb with a chloroformic acid ester are aprotic organic solvents, for example, 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 the compound of Formula llb, 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 t~ :

,~. . ', ' ' ' ~ '' ' . ` ". " ' ' , ., ' ' , " ' . ':, ' `: ,. ' ', ', "' ', ','"', ' ' ~lZ34~ M-10~1 mixture is maintained at a temperature between about 0C
and the reflux temperature of the solvent for from about 1 to about 96 hours. The thus obtained 1-(R~-oxycarbonyl)-

4-(naphthalenyloxy)piperidine of Formula Vll is isolated,

5 for example, by extraction into an organic solvent and -evaporation of the solvent,according to generally known procedures, and the R4-oxycarbonyl group cleaved by an appropriate method.
In the preferred embodiment of this invention, an N-lower alkyl- or N-phenyl(lower alkyl)-substituted com-pound of Formula llb is refluxed in methylene chloride with a slight excess, for example, from 1.01 to 1.3 equivalents, preferably about 1.1 equivalents, of 2,2,2-trichloroethyl chloroformate in the presence of a trace amount of a proton scavenger for from about 6 to about 24 hours at a temperature of from about 15 to about 40C, preferably at room temperature. The product is extracted into ether, washed with dilute acid and concentrated In vacuo. The re-sulting 1-(2,2,2-trichloroethoxycarbonyl)-4-(naphthaleny-loxy)piperidine is dissolved in a solvent selected fromacetic acid, aqueous acetic acid, a lower alkanol, such as methano1, an aqueous lower alkanol, and, preferably, a mix-ture of acetic acid, water and an ether, such as tetrahydro-furan. At a temperature of from about 0 to 50C, preferably at room temperature, from 1 to 5 equivalents, preferably about 2 equivalents, of 7inc dust is added gradually with stirring, and the reaction allowed to proceed for from about 1 to about 6 hours until gas evolution ceases.
The solvents are evaporated and the N-unsubstituted com-pound of Formula lla separated from the residual zincsalts by basification, extraction into an organic solvent, washing to remove water soluble impurities, conversion to a water-soluble acid addition salt, washing with or-ganic solvents to lemove neutral organic impurities and rebasification. The ,~J-unsubstituted compound is recrys-tallized by conventional methods, preferably in the form of its acid addition salt, from suitable solvents, ~ ' ~, . ~ :

;Z344 such as lower aliphatic alcohols, ketones, esters and combinations thereof.
Free bases of Formula ll prepared by the above-men-tioned method may be converted to the acid addition salts by reaction with a suitable acid according to generally known procedures.
The compounds of Formula I are prepared by reacting a piperdine derivative of Formula lla, wherein R2 is hydro- -ger~ with a small excess of an w-haloalkyl phenyl ketone or an w-halo-1-phenyl-1-alkanol of structure Vlll 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, 2 or more equivalents of the piperidine deriva-tive of Formula ll relative to compound Vlll may be used instead of the mineral base acid acceptor. The compounds of Formula I may also be prepared from the acid addition salt of the compound of Formula !la by reacting the acid addition salt with a compound of structure Vlll in the presence of at least 2 equivalents of the mineral base acid acceptor. The reaction mixture may be reacted over a wide range of temperatures. Generally, a reaction temperature of from about 20 to 180C is employed. The reaction is conducted over a period of from 1 to 4 days, during which time any evolved water may be collected.
As examples of suitable solvents for this reaction, there may be mentioned toluene~ xylene, chlorobenzene, methyl isobutyl ketone and lower aliphatic alcoholsJ such as ethanol, propanol and butanol.
After completion of the reaction, the product is isolated by conventional means, for example, the reaction mixture may be riltered and the solvent removed, isolating the product. AlternatelyJ the filtrate may be treated ~5 with an ethereal solution of a suitable mineral or organic acid to give the corresponding salt of the product. The 3 ~'~

crude product is filtered off, purified by recrystalliza-tion and dried. Suitable solvents for recrystallization are, for example, lower aliphatic alcohols, such as methanol, ethanol and isopropanol; ketones, such as ace-tone and butanone; nitriles, such as acetonitrile; andcombinations thereof.
The general method for the preparation of the com-pounds of Formula I can be represented by the following reaction scheme R ~
O + ha l o- ( CH2 ) n~Z~ R 1 ----lla ~ Vlll H

. ' (CH2)n-Z- ~ -R1 wherein n, R, R1 and Z are as hereinabove defined and halo is a reactive halogen, such as bromine, chlorine or iodine. ~ -Compounds of Formula Vlll are commercially available or may be prepared by methods well known in the art.
Compounds of Formula Vlll wherein Z is C=O may, for example, be prepared by reacting the appropriate w-haloalkanoyl halide and a (substituted)benzene in the presence of a Lewis acid, such as aluminum chloride, or by reacting a (4-substituted)phenyl Grianard reagent with an appropriate w-haloalkylnitrile. Compounds of Formula Vlll wherein Z ;
is CHOH may be prepared by reduction by means of chemical reducing agents or catalytic hydrogenation of the corres-ponding 1-(4-substituted)phenyl-W-haloalkanones of Formula - 10~ 1 3~

VIII prepared as descr7bed above or by reaction of a (4-substituted)phenyl Grignard reagent with an appropriate w-haloalkanaldehyde.
3-(4-Naphthalenyloxy-1-piperidyl)-1-phenylpropanones, compounds of Formula III wherein n is equal to 2, may also be prepared by reacting compounds of Formula II wherein R2 is hydrogen with an appropriate acetophenone and form-aldehyde.
~-(Naphthylenyloxy)-1-piperidinealkanols of Formula IV may be prepared by reduction of alkanones of Formula III.
Suitable methods for reducing ketones to alcohols are well known in the art, and include catalytic hydrogenation and reduction by chemical reducing agents.
For catalytic reduction, a ketone of Formula III may, for example, be dissolved in a solvent, such as acetic acid, ethyl acetate, or a lower aliphatic alcohol, such as methanol or isopropanol, and the solution agitated in the presence of hydrogen at from about 1 to about 4 atmos-pheres of pressure and room temperature, that is about 20-25C, in the presence of a suitable catalyst, such as platinum, platinum oxide or rhodium, until one equivalent of hydrogen is consumed.
Alternatively, the ketone of Formula III may be reduced by reaction with a suitable chemical reducing ~
25 agent. For example, the ketone may be refluxed in ether -for from 1 to 5 hours with a metal hydride, for example, lithium aluminum hydride or diborane, or reacted for from about 1/2 to 8 hours at a temperature of from 0C
to the reflux temperature of a lower aliohatic alcohol solvent, such as methanol or ethanol, with a metal boro-hydride, such as sodium borohydride or potassium boro-hydride, to yield an alcohol of Formula IV. Additional reagents suitable for the reduction of a ketone to an alcohol will be obvious to one skilled in the art.
Compounds of Formula I prepared in the form of free bases may be converted to their acid addition salts by reaction with a pharmaceutically acceptable acid.

M-lO~il ~lLlZ3~'~V

The optical isomers of optically active compounds of Formula I may be separated by means of any suitable resolv-ing agent. For example, the optical isomers of compounds of Formula I wherein Z is hydroxymethylene may be sepa-rated by using a (+)- or (-)-binaphthylphosphoric acid ;
derivative or a salt of said derivative and an optically active base by the method described by R. Viterbo et al., in Tetrahedron Letters 1971 (48), pp. 4617-20.

4-(2-NaphthalenYloxy)-1-(phenylmethyl)piperidine hydro-chloride To a stirred suspension of 1.80 9 (37.5 mmole) of pen-tane washed 50~ sodium hydride dispersion in 50 ml of dry dimethylformamide under argon is added a solution of 4.75 g (25.0 mmole) of 1-phenylmethyl-~-piperidinol in 20 ml of dry dimethylformamide followed by a solution of 3.83 g (26.2 mmole, 1.05 eq.) of 2-fluoronaphthalene in 20 ml `
of dimethylformamide. The mixture is heated at 75C for 23 hours, cooled, poured into ice water and extracted twice with ether. The extracts are washed with water and brine, dried over magnesium sulfate and filtered. The filtrate is treated with HCl/methanol and the resulting 4-(2-naphthalenyloxy)-1-(phenylmethyl)piperidine hydrochloride recrystalli~ed from butanone/methanol. M.P. 242-244C. -4-(1-Naphthalenyloxy)-1-phenylmethylpiperidine hydrochloride When in the procedure of Example 1, 1-fluoronaphtha- i~
lene is substituted for 2-fluoronaphthalene, 4-(1-naphthalenyloxy)-1-(phenylmethyl)piperidine hydrochloride is produced. M.P. 222-224C.

4-(5-Methoxy-1-naphthalenyloxy)-1-(phenylmethyl)piperidine hydrochloride When in the procedure of Example 1, 5-methoxy~
fluoronaphthalene is substituted for 2-fluoronaphthalene, 4-(5-methoxy-1-naphthalenyloxy)-1-(phenylmethyl)piperidine hydrochloride is produced.

.';. :

4-(1-~lethy1-2-naphthalenyloxy)-1-methylpiperidine hydro-chloride -:
When in the procedures of Example 1, 1-methyl-2-fluoronaphthalene is substituted for 2-fluoronaphthalene 5 and 1-methyl-4-piperidinol is substituted for 1-phenyl-methyl-4-piperidinol, 4-(1-methyl-2-naphthalenyloxy)-1-methylpiperidine hydrochloride is produced.

4-(4-Trifluoromethyl-2-naphthalenyloxY)-l-methylpiperidinol hydrochlor~de When in the procedure of Example 1J 4-trifluoromethyl-2-fluoronaphthalene is substituted for 2-fluoronaphthalene and 1-methyl-4-piperidinol is substituted for 1-phenyl-methyl-4-piperidinol, 4-(4-trifluoromethyl-2-naphthalenyl-oxy)-1-methylpiperidine hydrochloride is produced.

4-(5-Fluoro-1-naphthalenyloxy)-1-ethylpiperidine hydro-chloride When in the procedure of Example 1, 1,5-difluoro-naphthalene is substituted for 2-fluoronaphthalene and 1-ethyl-4-piperidinol is substituted for 1-phenylmethyl-4-piperidinol, 4-(5-fluoro-1-naphthalenyloxy)-1-ethylpiperi-dine hydrochloride is produced.

4-(2-Naphthalenyloxy)piperidine hydrochloride To a stirred solution of 64.6 9 (0.204 mole) of 4-(2-naphthalenyloxy)-1-phenylmethylpiperidine in 500 ml of methylene chloride is added ~7.0 ml (.268 mole) of 2,2,2-trichloroethyl chloroformate and about 200 mg.
of potassium carbonate. The mixture is stirred at room temperature for 48 hours and poured into a volume of ether and water. The organic phase is 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 is dissolved in a mixture of 250 ml of ace-tic acid, 250 ml of tetrahydrofuran and , ~ .
~lZ3~40 125 ml of water. ~8.5 9 (.436 mole) of zinc dust is added in portions with stirring and the exothermic reaction allowed to proceed for 2-1/2 hours. The mixture is fil-tered and the solvents are removed in vacuo. The residue is partitioned between ether and aqueous sodium hydroxide and the organic phase washed with water and extracted ;
with dilute aqueous hydrochloric acid. The acid extracts are washed with ether, made basic with sodium hydroxide and extracted into ether and toluene and the organic solu-tion washed~ dried over magnesium sulfate and concentrated in vacuo to yield 4-(2-naphthalenyloxy)piperidine, which -is redissolved in ethanol/ether and treated with dry HCl, and the hydrochloride salt recrystallized from butanone/
methanol. M.P. 229.5-231.5C.

~-(1-Naphthalenyloxy)piperidine hydrochloride When in the proceudre of Example 7, 4-(1-naphtha-lenyloxy)-1-phenylmethyl)piperidine is substituted for 4-(2-naphthalenyloxy)-1-phenylmethyl)piperidine, 4-(1-naphthalenyloxy)piperidine hydrochloride is produced.

4-(4-Trifluoromethyl-2-naphthalenyloxy)piperidine hydro-chloride When in the procedure of Example 7, 4-(4-trifluoro- ~ `
methyl-2-naphthalenyloxy)-1-methylpiperidine is substi-tuted fGr 4-(2-naphthalenyloxy-1-(phenylmethyl)-piper-idine, 4-(4-trifluoromethyl-2-naphthalenyloxy)piperidine hydrochloride is produced.
EXAMPLE 10 ;
' . , 4-(5-Fluoro-1-naphthalenyloxy)piperldine hydrochloride When in the procedure of Example 7, 4-(5-fluoro-1-naphthalenyloxy)-1-ethylpiperidine is substituted for 4-(2-naphthalenyloxy)-1-(phenylmethyl)piperidine, 4-(5-fluoro-1-naphthalenyloxy)piperidine is produced.

3~Z3~

4-(~-Methoxy-1-n3phthalenyloxy)piperidine hydrochloride A solution of 18.4 9 (50 mmole) of 4-(5-methoxy-1-naphthalenyloxy)-1-(phenylmethyl)piperidine in 10 ml of 1,2-dichloroethane is added gradually to a chilled solution of 65 mmole of vinyl chloroformate in 50 ml of 1,2-dichloroethane and the mixture stirred at room temperature for 4 hours and concentrated in vacuo.
The thus obtained 4-(5-methoxy-1-naphthalenyloxy)-1-(vinyloxycarbonyl)piperidine is stirred for 2 hours with 2N HCl in methanol to yield 4-(5-methoxy-1-naph-thalenyloxy)piperidine hydrochloride.

4-(1-Methyl-2-naphthalenyloxy)piperidine hydrochloride When in the procedure of Example 11 4-(1-methyl-2-naphthalenyloxy)-1-methylpiperidine is reacted with benzyl chloroformateJ the resulting 4-(1-methyl-2-naph-thalenyloxy)-1-(phenylmethoxycarbonyl)piperidine yields upon hydrolysis 4-(1-methyl-2-naphthalenyloxy)piperidine hydrochloride.
EXAMPLE 1~
4-~4-(2-Naphthalenyloxy)-1-piperidyll-1-phenyl-1-butanone hydrochloride A solution of 5.~7 g (25 mmoles) of 4-(2-naphtha-lenyloxy)piperidine, 5.0 9 (27.4 mmole) of 4-chloro-1-phenyl-1-butanone, 0.1 g of potassium iodide and 4.5 g potassium bicarbonate in 100 ml of toluene is heated for 48 hours with stirring on a steam bath. The mixture is partitioned between 100 ml portions of methylene chloride/
ether and water and the organic phase dried over ~gS04.
A solution of an excess of HCl in ether is added and the resulting precipitate recrystallized from methanol/
butanone to yield 4-(2-naphthalenyloxy-1-piperidyl)-1 phenyl-1-butanone hydrochloride.

. . . .. ..... ...... .

M-10~1 34~

4-[4-(2-Naphthalenyloxy)-1-piperidyll-1-(4-fluorophenyl)-1-butanone hydrochloride When in the procedure of Example 13, 4-chloro-1-(4-fluorophenyl)-1-butanone is substituted for 4-chloro-1-phenyl-1-butanone; 4-[4-(2-naphthalenyloxy)-1-piperidyl]-1-(4-fluorophenyl)-1-butanone hydrochloride is produced.
M.P. 219-221.5C.

4-r4-(1-Naphthalenyloxy)-1-piperidyl1-1-(4-fluorophenyl)-1-butanone hydrochloride When in the procedure of Example 13, 4-chloro-1-(4-fluorophenyl)-1-butanone is substituted for 4-chloro-1-phenyl-1-butanone and 4-(1-naphthalenyloxy)piperidine hydrochloride is substituted for 4-(2-naphthalenyloxy)-piperidine hydrochloride, 4-[4-(1-naphthalenyloxy)-1-piperidyl]-1-(4-fluorophenyl)-1-butanone hydrochloride is produced. M.P. 220-222.5 C.

3-~4-(5-Methoxy-1-naphthalenyloxy)-1-piperidyl1-1-(4-chlorophenyl ~ 1-propanone hydrochloride When in the procedure of Example 1~, 4-(5-methoxy-1-naphthalenyloxy)piperidine hydrochloride is substitutedfor 4-(2-naphthalenyloxy)piperidine hydrochloride and ~-chloro-1-(4-chlorophenyl)-1-propanone substituted for 4-chloro-1-phenyl-1-butanone, 3-[4-(5-methoxy-1-naphthalenyl-oxy)-1-piperidyl]-1-(4-chlorophenyl)-1-propanone hydro-chloride is produced.

5-r4-(2-Naphthalenyloxy)-1-piperidyll-1-(4-methylphenyl)-1-pentanone hydrochloride When in the procedure of Example 1~, 5-chloro-1-(4-methylphenyl)-1-pentanone is substituted for 4-chloro-1-phenyl-1-butanone, 5-~4-(2-naphthalenyloxy-1-piperidyl]-1-(4-methylphenyl)-1-pentanone hydrochloride is produced.

~ " ": ~

,; - ...... : . .

~Z3~

4-[4-(l-Methyl-2-naphthalenyloxy)-l-piperidy~ (4 fluorophenyl)-1-butanone A solution of 3.47 9 (12.5 mmole) of 4-(1-methyl-2-naphthalenyloxy)piperidine, ~.63 9 (13.1 mmole) o-F 4-chloro-1-(4-fluorophenyl)-1-butanone, 5.2 9 (52 mmole) of potassium bicarbonate and a pinch of potassium iodide in 60 ml of toluene is heated at reflux for 80 hours. The mixture is partitioned between toluene and water and the organic phase washed with brine, dried over magnesium sul-fate, and concentrated In vacuo to yield 4-[4-(1-methyl-2-naphthalenyloxy)-1-piperidyl]-1-(4-fluorophenyl)-1-butanone.

6-~4-(4-Trifluoromethyl-2-naphthalenyloxy)-1-plperidyll-1-~Ll-methoxyphenY1,-1-hexanone When in the procedure of Example 18, 4-(4-trifluoro-methyl-2-naphthalenyloxy)piperidine is substituted for 4-(1-methyl-2-naphthalenyloxy)piperidine and 6-bromo-1-~4-methoxyphenyl)-1-hexanone substituted for 4-chloro-1-(4-fluorophenyl)-1-butanone, 6-[4-(4-trifluoromethyl-2-naphthalenyloxy)-1-piperidyl]-1-(4-methoxyphenyl)-1-hexanone is obtained.

a-(4-Fluorophenyl)-4-(1-methyl-2-naphthalenyloxy)-1-piperidinebutanol When in the procedure of Example 18, 4-chloro-1-(4-fluorop'nenyl)butanol substituted for 4-chloro-1-(4-fluorophenyl)-1-butanone, G-(4-fluorophenyl)-4-(1-methyl-2-naphthalenyloxy)-1-piperidinebutanol is produced.
EXA~IPLE 21 2-Phenyl-4-(5-fluoro-1-naphthalenyloxY)-1-piperidine-propanol When in the procedure or Example 18, 4-(5- fluoro-1-naphthalenyloxy)piperidine is substituted for (1-methyl-2-naphthalenyloxy)piperidine and ~-bromo-1-phenyl-propanol substituted for 4-chloro-1-(4-fluorophenyl)-1-butanone, a-phenyl-4-(5-fluoro-1-naphthalenyloxy)-1-piperidinepropanol is obtained.

-- . ~ - ~, . , ., -,.: . ~ . . . ~ . :: :
.. . , ., .. ,~ , ^ , .

M-lO~il 1~2;344t) 3-L4-(5-Methoxy-1-naphthalenyloxy~-1-piperidyll-1-(4-fluorophenyl)-1-propanone A mixture of 25.5 9 (0.1 mole) of 4-(5-methoxy-1-naphthalenyloxy)piperidine, 9 9 (0.3 mole) of paraform-aldehyde and 13.8 9 (0.1 mole) of 4'-fluoroacetophenone in 100 ml of isopropyl alcohol containing 2 drops of concentrated hydrochloric acid is refluxed for 24 hours.
The mixture is filtered and the filtrate concentrated to about 100 ml and cooled. The resulting precipitate is recrystallized from ethanol to give 3-[4-(5-methyl-1-naphthalenyloxy)piperidyl-1-(4-fluorophenyl)-1-propanone.

a-(4-Fluorophenyl)-4-(2-naphthalenyloxy)-1-piperidine-butanol To 8.o g (0.02 mole) of 4-[4-(2-naphthalenyloxy)-1-piperidyl]-1-(4-fluorophenyl)-1-butanone HCl in 50 ml of methanol is added 1.1 9 (0.02 mole) of sodium methoxide and then 2.7 9 (0.05 mole) of potassium borohydride and the mixture stirred at room temperature for 2 hours.
The methanol is removed at reduced pressure on a steam bath after which 50 ml of 10~ sodium hydroxide solution is added. The mixture is stirred for 15 minutes and 100 ml of chloroform is added. Stirring is continued for 1/2 hour. The chloroform layer is separated and combined with two 25 ml chloroform extracts of the aqueous phaseJ
washed with water and with brine, dried over MgS04~ fil-tered and concentrated to a solid. The solid material is recrystallized from ethanol/water to give z-(4-fluoro-phenyl)-4-(2-naphthalenyloxy)-1-piperidinebutanol.

~-(4-Methoxyphenyl)-4-~4-trifluoromethyl-2-naphthalenYl-oxy)-1-piperidinehexanol When in the procedure of ~xample 23~ 6-[4-(4-tri-fluoromethyl-2-naphthalenyloxy)-1-piperidyl]-1-(4-methoxy-phenyl)-1-hexanone hydrochloride is substituted for 4-r4-(2-naphthalenyloxy)-1-piperidyl]-1-(4-fluorophenyl)-1-~3 ~

butanone, ~-(4-methoxyphenyl)-~-(4-trifluoromethyl-1-naphthalenyloxy)-1-piperidinehexanol is obtained.

Tablet Formulation An illustration of a representative tablet formula-tion of an active compound of this invention is as follows:
Per Tablet (a) 4-[(2-naphthalenyloxy)-1- 25.0 mg piperidyl~-1-(4-fluorophenyl)-1-butanone hydrochloride (b) Wheat starch 3.5 mg 10 (c) Lactose 10.0 mg (d) Magnesium stearate 0.5 mg A granulation obtained upon mixing lactose with the starch and granulated starch paste is dried, screened and mixed with the active ingredient and magnesium stearate.
The mixture is compressed into tablets weighing 39.0 mg each.

Gelatin Capsule Formulation An illustrative composition for hard gelatin capsules 20 is as fol10ws:
Mq (a) 4-~4-(2-naphthalenyloxy)-1- 10 piperidyl~ (4-fluorophenyl)-1-butanone hydrochloride (b) Talc 5 (c) Lactose 100 The formulation is prepared by passing the dry powders of (a) and (b) through a fine mesh screen and mixing them well. The powder is then filled into hard gelatin cap-sules at a net fill of 115 mg per capsules.
EXAM~LE 27 Injectable SusDension Formulation An illustrative composition for an injectable sus-pension is the following 1 ml ampul for an intramuscular injection.

- - . , . . . : . : . . . .

, M-1031 ~` ~ Z 3 ~ ~3 Weiqht Percent (a) 4-[4-(2-naphthalenyloxy)-1- 1.0 piperidyl]-1-(4--fluorophenyl)-1-butanone (particle size <10~) (b) Polyvinylpyrrolidone (M.W. 25000) 0.5 (c) Lecithin 0.25 (d) Water for injection ~o make 100.0 The materials (a)-(d) are mixedJ homogenized, and filled into 1 ml ampules which are sealed and autoclaved 20 minutes at 121C. Each ampul contains 10 mg per ml of novel compound (a).

Claims

The embodiments of the invention in which an exclu-sive property or privilege is claimed are defined as follows:

1. A process for the preparation of a compound of the formula wherein n is an integer of from 2 to 5; R is selected from hydrogen, halogen, straight or branched chain alkyl of from 1 to 4 carbon atoms, straight or branched chain alkoxy of from 1 to 4 carbon atoms and trifluoromethyl;
R1 is selected from hydrogen, halogen, straight or branched alkyl of from 1 to 4 carbon atoms, and straignt or branched alkoxy of from 1 to 4 carbon atoms; and Z is selected from carbonyl and hydroxymethylene; an individual optical isomer, or a pharmaceutically acceptable acid addition salt thereof, which comprises a) alkylating a compound of the formula M-103l-CA

or an acid addition salt thereof with a compound of the formula wherein halo is C1, Br or 1, and n, R, R1 and Z have the meanings defined above, in a suitable solvent in the presence of a base and optionally in the presence of a catalytic amount of potassium iodide, for from about 24 to about 96 hours at a temperature of from about 20° to about 180°C, or b) when Z is hydroxymethylene, reducing a thus obtained compound wherein Z is carbonyl, and c) when a pharmaceutically acceptable salt is desired, reacting the thus obtained compound with a pharmaceutically acceptable acid.

2. A compound of the formula wherein n, R, R1, and Z have the meanings defined in claim 1, an individual optical isomer, or a pharmaceutically acceptable acid addition salt thereof, when prepared by the process of claim 1.

3. The process according to claim 1 wherein Z is carbonyl,which comprises a) alkylating a compound of the formula or an acid addition salt thereof with a compound or the formula wherein halo, n, R, and R1 have the meanings defined in claim 1, in a suitable solvent in the presence of a base and optionally in the presence of a catalytic amount of potasstum iodide, for from about 24 to about 96 hours at a temperature of from about 20° to about 180°C, and b) when pharmaceutically acceptab1e salt is desired, reacting the thus obtained compound with a pharmaceutically acceptable acid.

4. A compound of the formula wherein n, R and R1 have the meanings defined in claim 3, when prepared by the process of claim 3.

5. The process according to claim 1 wherein n is 3.

6. A compound of the formu1a wherein R, R1 and Z have the meanings defined in claim 5, optical isomer, or a pharmaceutically acceptable acid addition salt thereof, when prepared by the process of claim 5.

7. The process according to claim 1 wherein R1 is fluorine.

8. A compound of the formula wherein n, R, and Z have the meanings defined in claim 7, an individual optical isomer, or a pharmaceutically acceptable acid addition salt thereof, when prepared by the process of claim 7.

9. The process according to claim 1 wherein R is selected from hydrogen and halogen.

10. A compound of the formula wherein n, R, R1, and Z have the meanings defined in claim 9, an individual optical isomer, or a pharmaceuti-cally acceptable acid addition salt thereof, when pre-pared by the process of claim 9.

11. The process according to claim 1 for the pre-paration of 4-[4-(1-naphthalenyloxy)-1-piperidyl]-1-(4-fluorophenyl)-1-butanone or a pharmaceutically acceptable acid addition salt thereof, which comprises a) alkylating 4-(1-naphthalenyloxy)piperidine or an acid addition salt thereof with a compound of the formula wherein halo is C1, 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 about 24 to about 96 hours at a temperature of from about 20° to about 180°C, and b) when a pharmaceutically acceptable salt is desired, reacting the thus obtained compound with a pharmaceutically acceptable acid.

12. The compound 4-[4-(1-naphthalenyloxy)-1-piperidyl]
1-(4-fluorophenyl)-1-butanone or a pharmaceutically acceptable acid addition salt thereof when prepared by the process of claim 11.

13. The process according to claim 1 for the prepa-ration of 4-[4-(2-naphthalenyloxy)-1-piperidyl]-1-(4-fluorophenyl)-1-butanone or a pharmaceutically acceptable acid addition salt thereof, which comprises a) alkylating 4-(2-naphthalenyloxy)piperidine or an acid addition salt thereof with a compound of the formula wherein halo is C1, Br or l, in a suitable solvent in the presence of a base and optionally in the presence of a catalytic amount of potassium iodide, for from about 24 to about 96 hours at a temperature of from about 20° to about 180°C, and b) when a pharmaceutically acceptable salt is desired, reacting the thus obtained compound with a pharmaceutically acceptable acid.

14. The compound 4-[4-(2-naphthalenyloxy)-1-piperidyl]-1-(4-fluorophenyl)-1-butanone or a pharmaceutica1ly acceptable acid addition salt thereof, when prepared by the process of claim 13.