NZ194248A - Derivatives of 4-(naphthalenyloxy)piperidines;intermediates;pharmaceutical compositions - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number 1 94248 19424 8 Friafily «. h •' & ■ ..

•Completa Specification Fdod: C\a**:c?&ftk P£W?-'/W£.

I • i b i a i i Pub!icstion Deto: ... P.O. -Na /*?£?. • ■ • • 7-So .J ill is j b & "• ■* ™SS5' No.: Date: NEW ZEALAND PATENTS ACT, 1953 COMPLETE SPECIFICATION "4-(NAPHTHALENYLOXY)PIPERIDINE DERIVATIVES" IV We, RICHARDSON-MERRELL INC., a corporation organized under the laws of the State of Delaware, United Stated of America, of Ten Westport Road, Wilton, Connect icut^^^ 06 89 7, United States of America, L \ ^ \ % hereby declare the invention for which Jlx/ we pray that a patent rfijpy ' be granted to kk^us, and the method by which it is to be performed, to be particularly described in and by the following statement:- - 1 - (followed by page la) M-icrn 194248 -i<*~ 4-(NAPHTHALENYLOXY)PI PER ID INE DERIVATIVES FIELD OF THE INVENTION This invention relates to novel derivatives of 4-(naphtha 1eny1oxy)piperidines and methods for their pre-5 paration. More particularly it relates to new 4-naphthal-enyloxypiperidines, useful as chemical intermediates, and their N-(w-benzoylal kyl ) and N-(w-hydroxy-^-pheny lal ky 1 ) derivatives, useful as neuroleptic tranquilizers whose use does not induce significant extrapyramidal side effects. 10 DESCRIPTION OF THE PRIOR ART 1-Phenyl-uu-( 1-piperidyl )al kanones constitute an important class of central nervous system depressants. Various compounds of this class are claimed, for example, in U.S. patents 3,438,991; 3,518,276; 3,576,810; 3,816,433; 15 3,888,867 and 3,907,812. Although compounds of this type are often found to have potent antipsychotic activity, their use has been limited by' the occurrence of serious extrapyramidal side effects and transient hypotension. •t has now been discovered that the novel uj-(4-20 naphtha 1eny1oxy-l-piperidy1)-1-pheny1alkanones and the cor respond ing naphthalenyloxy-a-pheny1 -1-p i per i d i na1kanols of this invention display potent antipsychotic activity without inducing significant extrapyramidal side effects and with little effect on blood pressure. 25 SUMMARY OF THE INVENTION Novel compounds of formula 4 * 7 W24 8 Formula I (CHs)n-Z-@-R: wherein n is an integer of from 2 to 5; R is hydrogen, alkyl, alkoxy, halogen or trif1uormethy1; Ri is hydrogen, alkyl, alkoxy or halogen; and Z is carbonyl or hydroxy-methylene, are useful as antipsychotic agents. These anti psychotic compounds may be prepared from intermediates of Formula II Formula I I wherein R2 is hydrogen, lower alkyl or phenyl(lower alky!, 10 and R has the meaning defined above. Compounds of Formula 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 isomers of the 15 compounds of Formula I.

DETAILED DESCRIPTION OF THE INVENTION Compounds of Formula I include UJ-[4-(l- and 2-naph-tha]eny1oxy-i-piperidyl)]-l-(4-substituted)phenyl-l-alkanones of Formula Ml v M-lODJr 194248 and 4-(l- and 2-naphtha1enyloxy)-a-(4-substituted)phenyl -1-piper idinea1kanols of Formula IV Formula IV OH (CH2)n-CH-<^>-R: wherein n, R and Ri have the meanings defined above, their individual optical isomers, and their pharmaceutical 1y acceptable acid addition salts.

As used herein, alkyl is taken to mean straight or branched chain alkyl groups having from 1 to 4 carbon 10 atoms. Illustrative examples of alkyl groups are methyl, ethyl, propyl and tertiary butyl. Lower 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 15 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 position of the naphthalene ring system other than the position occu-20 pied by the (4-piperidy1oxy) substituent.

Preferred embodiments of this invention are compounds of Formula I wherein Z is carbonyl; also preferred are embodiments of this invention wherein n is equal to 3.

■■Mr- 1 OJll^ 19424 Further preferred embodiments of this invention are compounds of Formula I wherein R is selected from hydrogen and halogen. Preferred embodiments of this invention also include compounds of Formula I wherein Ri is halogen and especially fluorine.

Exemplary compounds of Formula I are: 4- [ 4- (1-na phtha 1 eny 1 oxy) -1- p i per idy I ]-l - ( 4- f I uoro phenyl) 1-butanone, 4-[4-(2-naphtha1eny1oxy)-1-p i per i dy1]-1-(4-f1uorophenyl)-1-butanone, 4-[4-(6-ch1oro-2-naphthalenyloxy)-l-piperidyl]-l-(4-fluoro-phenyl)-1-butanone, 3-[4-(5-methoxy-l-naphtha 1 eny 1 oxy) - 1-p i per i dy 1 ] -1- ( 4-ch1orophenyl)-1-propanone, 4-[4-(2-na phtha1eny1oxy)-1-p i per i dy1]-l-(4-methy1 phenyl)-1-butanone, -[4-(1-methy1-2-naphtha 1enyloxy)-1-pi per idyl]-1-(4-ethoxy-pheny1)-1-pentanone, 4-[4-(8-methoxy-2-naphthalenyloxy)-l-piper idyl]-1-pheny1 -1-butanone, 6-[4-(5-f1uoro-1-naphthalenyloxy)-l-piperidyl]-1-(4-f1uoro-phenyl)-1-hexanone, 4-[4-(2-1r i f1uoromethy1-l-naphthalenyloxy)-l-piperidinyl]-l-(4-bromophenyl)-1-butanone, 4-(1-naphtha 1eny1oxy)-a-(4-f1uorophenyl)-1-p i per id i ne-butanol, 4-(2-naphtha 1eny1oxy)-a-(4-f1uorophenyl)-l-piperidine-butanol, 4-(4-tr i f1uoromethy1-2-na phtha1eny1oxy)-a-phenyl-1-p i per i-d i nebutano1, 4-(6-bromo-2-na phtha1eny1oxy)-a-(4-bromophenyl)-1-p i per i-d i nepropanol, 4-(7-i sopropyl-1-naphtha1enyloxy)-a-(4-f1uorophenyl)-1-p i per i d i nepentano 1, 4-(3~ethoxy-2-naphtha 1eny1oxy)-a-(4-methoxyphenyl)-1-pi per id i nebutano1, 4-(2-na phtha1eny1oxy-a-(4-ethyl phenyl)-l-piperidine-hexano1, 4-(8-fluoro-1-naphtha 1eny1oxy)-a-(4-fluorophenyl)-1-piperidinebutano1, and 4-(2-methy 1-1-naphtha1eny1oxy)- a-(phenyl)-1-p i per i d i nebutano 1 .

The invention also includes the pharmaceutica11y 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, glycol ic, lactic, pyruvic, malonic, succinic, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxyma1eic, dihydroxyma1eic, benzoic, pheny1acetic, 4-aminobenzoic, 4-hydroxybenzoic, anthranilic, cinnamic, salicylic, aminosalicylic, 2-phenoxybenzoic, 2-acetoxybenzoic and mandelic acids; and sulfonic acids, such as methanesu1fonic, 2-hydroxy-ethanesu 1 fon ic and jd-tol uenesu 1 fon ic acids.

Novel intermediates for the preparation of compounds of Formula I are compounds of Formula II wherein R has the meaning defined above, and R2 is hydrogen, lower alkyl or phenyl(lower alkyl) and acid addition salts thereof. Preferred embodiments of Formula II are compounds wherein R2 is hydrogen, methyl or phenylmethyl and those wherein R is hydrogen or halogen.

Exemplary compounds of Formula II include-. 4-(1-naphtha 1eny1oxy)pi per id i ne, 4- (2-na phtha1eny1oxy)p i per i d i ne, 4-(6-ch1oro-2-naphtha 1eny1oxy)p i per i d i ne, I I R2 - M-1031-" 1 9424 8 4-(5-methoxy-l-naphtha 1eny1oxy)pi per id i ne, 4-(1-methyl-2-naphtha 1enyloxy)p i per i d i ne, 4-(8-methoxy-2-naphthalenyloxy)piper id ine, 4-(5-f1uoro-1-na phthalenyloxy)p i per i d i ne, 4-(2-1r i fluoromethy1 -1-naphtha 1enyloxy)pi per i d i ne, 4-(6-bromo-2-naphtha 1eny1oxy)pi per id ine, 4-(7-i sopropy1-1-naphtha 1 en y1oxy)p i per i d ine, 4-(4-tr i f1uoromethy1-2-naphtha 1eny1oxy)pi per i d i ne, 4- (3-ethoxy-2-na phtha1enyloxy)p i per i d i ne, 10 4-(8-fluoro-1-naphtha 1eny1oxy)p i per i d i ne, 4-(2-methyl-1-na phtha1eny1oxy)p i per i d i ne 1-methy1 - 4-(1-na phtha1eny1oxy)p i per i d i ne, l-methyl-4-(6-chloro-2-naphthalenyloxy)piperidine, 1-methy1-4-(1-methy1-2-naphtha 1enyloxy)pi per i d ine, 15 1-methy1-4-(4-tr i f1uoromethy1-2-naphtha 1eny1oxy)p i per i d i ne, l-ethyl-4-(5-fluoro-l-naphthalenyloxy)piperidine, 1-methy1-4-(7-isopropy1-1-naphtha 1enyloxy)pi per id ine, 1-propyl-4-(8-methoxy-2-naphthalenyloxy)p i per i d i ne, 1-(phenyl methyl)- 4-(2-naphtha 1eny1oxy)p i per i d i ne, 20 1-(2-phenyl ethyl)-4-(5-methoxy-l-naphtha 1eny1oxy)p i per i-dine, 1-(phenylmethyl)-4-(2-tr i f1uoromethy1 -1-naphtha 1enyloxy)-pi per id ine, 1-(phenyl methyl)- 4-(6-bromo-2-naphtha 1eny1oxy)p i per i d i ne, 25 1~(phenyl methyl)- 4-(3-ethoxy-2-naphtha 1eny1oxy)piper id ine, 1-(3-phenylpropy1)- 4-(8-f1uoro-1-naphtha 1eny1oxy)p i per i-dine, and their acid addition salts.

The novel compounds of Formula 1 are antipsychotic agents useful when administered alone or in the form of 30 pharmaceutical preparations containing the novel compounds in combination with a pharmaceutical carrier as neuroleptic tranquilizers in warm blooded animals. Neuroleptic tranquilizers are useful for treatment of patients showing symptoms of psychoses, such as schizophrenia, or of 35 severe anxiety, agitation or aggressiveness. Such agents have a tranqui1izing effect on psychomotor activity, inducing a state of general quiescence in the patient without inducing sleep. Patients suitable for treatment with vM.-m-s'L 194248 antipsychotic compositions 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 humans.

Pharmaceutica1 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, parenteral 1y, for example, intraperitonea11y, intramuscularly or sub-10 cutaneously, or topically, for example, transderma11y or transmucosa11y. 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 15 composition and the body weight of members of the patient population to be treated. The treatment of a patient in need of tranqui1izing will provide from 0.002 to 100 mg/kg of body weight of the patient per day to achieve the desired tranqui1izing effect. For a human patient 20 this degree of tranqui1ization may be achieved by means of an antipsychotic composition in the form of tablets containing 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 25 achieve a comparable neuroleptic effect in smaller species of animals.

The compounds of general Formula 1, together with suitable pharmaceutical carriers, can be in the form of solid unit dosage forms such as tablets, capsules and 30 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, 35 binders, such as acacia, corn starch or gelatin; disintegrating agents, such as corn starch, guar gum or alginic acid; lubricants, such as stearic acid or magnesium -M-10^ - 8. 1942 4 8 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 5 sterile liquid, such as an oil, water, an alcohol or mixtures thereof, with or without the addition of a pharmaceu-tically suitable surfactant, suspending agent, or emulsifying agent, for oral, topical or parenteral administration.

For liquid preparations, the compounds of Formula I 10 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 glycerides; with alcohols, such as ethanol, isopropanol 15 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-20 tions of the soft gelatin type and suppositories. Water, saline, aqueous dextrose and related sugar solutions and glycerols, such as po1yethy1eneg1yco1, may be employed in the preparation of liquid formulations which may suitably contain suspending agents, such as pectin, carbomers, 25 methyl cellulose, hydroxypropy1 cellulose or carboxy- methyl cellulose, as well as buffers and preservatives.

Illustratively, when 4-[4-(2-naphtha 1eny1oxy)-1-p i per i dy1]-1-(4-f1uoropheny1)-1-butanone hydroch1 or i de was administered intraperitoneal1y to mice at a dosage 30 of 0 .06 mg/kg the aggregate toxicity of _d-amphetami ne was inhibited in 50^ of the mice tested according to the procedures disclosed by J. Burn et al., A rch. Int. Pharmacodyn. 113* 290-5 (1955).. thus demonstrating antipsychotic effectiveness, whereas a dosage level of 0.98 35 mg/kg of the known tranquilizer chlorpromazine is required to attain a similar level of response. Similarly, compounds of this invention evince neuroleptic activity ~M- 10>3r*- 19424 8 through the inhibition of pernicious preening in mice tested according to the method disclosed by A. Kandel et a l ., Fed. Proc., 19 (1, Pt. 1), 24 (i960).

The neuroleptic potency of these compounds is accom-5 panied by a reduced tendency to produce extrapyramidal side effects in patients treated with a neuroleptica1ly 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-10 1eny1oxy)-1-piperidy1]-1-(4-f1uoropheny1)-1-butanone hydrochloride was administered intraperitonea11y to mice, a dosage of J>k.O mg/kg was required to counteract the behavioral effects of apomorphine in 30% of the mice tested according to the general method disclosed by 15 P.A.J. Janssen et al ., in A rzne i m-Forsch. 10, 1003 (i960), whereas only 1.4 mg/kg of ch1orpromazine was required to attain a similar effect.

Compounds of Formula I are prepared by alkylation of intermediate compounds of Formula I la, Formu1 a -N-H which represent compounds of Formula II wherein R2 is hydrogen and R has the above-identified meaning. Compounds of Formula lla are themselves prepared by dealkyla-tion or debenzy1 ation of compounds of Formula Mb, Formu la Mb -M 1031- ,o 1942 4 8 wherein R3 is lower alkyl or phenyl(lower alkyl) and R has the above-defined meaning, which represent compounds of Formula II wherein R2 is lower alkyl or phenyl(lower alkyl). It is thus apparent that all of the compounds 5 of Formula II are useful intermediates for the pharmaceutical ly useful compounds of Formula I. Compounds of Formula II are also new and represent a part of this i nvent i on .

Compounds of Formula lib are prepared by reaction 10 of an N-substituted-4-piperidinol salt of Formula V 0"M+ Formula V T 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 VI Formula VI —m-I©5"r~ 194243 wherein R has the meaning defined above, to produce a l-(lower alkyl) or 1-pheny1(1ower alkyl)-4-naphtha1enyloxy-piperidine of Formula lib. The compounds of Formula 11a, wherein R2 is hydrogen, are prepared by dealkylation of N-substituted compounds of Formula lib by means of a chloro- 0 II formic acid ester of Formula R40C-C1, wherein R4 is 2,2,2-trichloroethyl, vinyl, substituted vinyl, benzyl, substituted benzyl or cycloalkyl, which is reacted with the compound of Formula lib in the presence of a proton scavenger, to produce a 1-(R4-oxycarbony1)-4-(naphthan1eny1oxy)piper-id i ne of Formula VII wherein R and R4 have the meanings defined above, and removal of the R4-oxycarbony1 group by means of a mild reducing agent, such as zinc dust in acetic acid or methanol, or by acid hydrolysis, as illustrated by the followi ng: 0 IN I o=c-o-r4 Formula VI + V VI I I b reduct i on or hydrolysis 0 0 VI I H 0=C-0R4 -M 103 X 194248 Naphthalene fluorides of Formula VI are well known and may be prepared by methods well known in the art, for example by the methods described by VI. Adcock et al., in J. Am. Chem. Soc. 82(2), 386-390 (ig6j) and in J. Am. Chem. 5 Soc. 28(7), 1701-1711 (1976).

Piperidinol salts of Formula V are prepared by reacting the corresponding 1-lower alkyl- or 1-phenyl(lower-alky 1)-4-piperidinol with a strong base, such as an alkali metal hydride, an alkali metal amide or alkyl 10 lithium 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 about 50° to about 200°C or at the boiling temperature of the solvent for from about 1 to 15 about 24 hours. Suitable solvents include tetrahydrofuran, dimethoxyethane, diglyme, dioxane, hexamethylphosphorus triamide, dimethy1acetamide, dimethy1sulfoxide, 1-methyl-2-pyrrol idone, sulfolane and, espec i a 11 y, d imethy 1 formamide.

The reaction is quenched and the resulting N-substitu-20 ted compound of Formula lib or its acid addition salt is isolated by conventional means, for example, the reaction mixture may be filtered and the solvent removed, isolating the product, which is purified by recrysta11ization and dried. Suitable solvents for recrysta11 ization are, for 25 example, lower aliphatic alcohols, such as methanol,' et'hanol and isopropanol; ketones, such as acetone and butanone; esters, such as ethyl acetate; hydrocarbons, such as hexane; and combinations thereof.

The thus prepared 1-lower alkyl- or 1-pheny1(lower-30 a 1 ky 1 )-4-( naphtha leny 1 oxy) p i pe r i d i ne of Formula Mb 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 VM, which is subsequently cleaved to yield the corresponding 1-unsubstituted-4-(naph-35 tha1eny1oxy)piperidine of Formula I la. Suitable chloroformic acid esters are those which yield R4-oxycarbony1 --M-iojr" 1942 4 8 substituents which may be cleaved from the nitrogen atom of the compound of Formula VI I hydrolytica11y or by reducing conditions under which the naphthalene ring is not hydrogenated. Such chloroformic acid esters include the 5 2,2,2-trichloroethyl ester, which may be cleaved by reduction with zinc dust or by electrolysis; the benzyl ester, benzyl esters substituted by phenyl, methoxy, methyl, phenylazo, cyano, bromo or chloro, vinyl esters, and cyclo-alkyl esters, such as the cyclohexyl, cyclopentyl, ada-10 mantyl and isobornyl esters, which may be cleaved by acid hydrolysis by means of strong acids, such as hydrochloric or hydrobromic acids, or by means of mild acids, such as trif1uoroacetic acid, in suitable solvents. Chloroformic acid esters suitable for displacing alkyl and benzyl sub-15 stituents from tertiary amines and methods suitable for the cleavage of the various R4-oxycarbony1 groups from the nitrogen atoms are described by M. Bodanszky et al., in Pept ide S ynthes i s, 2nd Edition (John Wiley & Sons) p. 21-37 (1976) and by R. Olofson et al. in U.S. patent 20 3.905,981, which are hereby incorporated by reference.

The preferred chloroformic acid ester for the dealkylation of compounds of Formula II wherein R2 is lower alkyl or pheny1(1ower alkyl) is 2,2,2-1richloroethy 1 ch1oroformate.

Suitable solvents for the reaction of an N-substituted 25 compound of Formula lib 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, dich1oroethane and methylene chloride, 30 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%-^fo by weight of the amount of the compound of Formula lib, of a proton scavenger, which may be an inorganic base, such as sodium 35 or potassium carbonate, a strong organic base, such as triethy1 amine, or a mixture thereof. The reaction <-kU4©^r— 1942 4 8 mixture is maintained at a temperature between about 0°C and the reflux temperature of the solvent for from about 1 to about 96 hours. The thus obtained 1-(R4-oxycarbony1)-4-(naphtha 1eny1oxy)piperidine of Formula VII is isolated, 5 for example, by extraction into an organic solvent and evaporation of the so 1 vent, accord i ng to generally known procedures, and the R4-oxycarbony1 group cleaved by an appropriate method.

In the preferred embodiment of this invention, an 10 N-lower alkyl- or N-pheny1(lower a 1kyl)-substituted compound of Formula lib is ref1uxed 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 ch1oroformate in the presence of a trace amount of a 15 proton scavenger for from about 6 to about 24 hours at a temperature of from about 15° to about 40°C, preferably at room temperature. The product is extracted into ether, washed with dilute acid and concentrated _i_n vacuo. The resulting l-(2,2,2-trich1oroethoxycarbony 1)-4-(naphthaleny-20 1oxy)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 tetrahydro-furan. At a temperature of from about 0° to 50°C, preferably 25 at room temperature, from 1 to 5 equivalents, preferably about 2 equivalents, of zinc 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-30 pound of Formula lla separated from the residual zinc salts by basification, extraction into an organic solvent, washing to remove water soluble impurities, conversion to a water-soluble acid addition salt, washing with organic solvents to remove neutral organic impurities and 35 rebasification. The N-unsubstituted compound is recrys-tallized by conventional methods, preferably in the form of its acid addition salt, from suitable solvents, r(T -X- 194248 such as lower aliphatic alcohols, ketones, esters and combinations thereof.

Free bases of Formula II prepared by the above-men-tioned method may be converted to the acid addition salts 5 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 I la, wherein Rs is hydrogen, with a small excess of an UJ-haloalkyl phenyl ketone 10 or an iu-ha 1 o- 1-pheny 1 - 1-a 1 kanol of structure VIM 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 15 desired, 2 or more equivalents of the piperidine derivative of Formula II relative to compound VIII 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 Ma by reacting the acid 20 addition salt with a compound of structure VIII 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 180°C is employed. The 25 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 alcohols, such 30 as ethanol, propanol and butanol.

After completion of the reaction, the product is isolated by conventional means, for example, the reaction mixture may be filtered and the solvent removed, isolating the product. Alternately, the filtrate may be treated 35 with an ethereal solution of a suitable mineral or organic acid to give the corresponding salt of the product. The -M ■ 1033- -X- 194248 crude product is filtered off, purified by recrysta11iza-tion and dried. Suitable solvents for recrysta11ization are, for example, lower aliphatic alcohols, such as methanol, ethanol and isopropanol; ketones, such as acetone and butanone; nitriles, such as acetonitri1e; and combinations thereof.

The general method for the preparation of the compounds of Formula I can be represented by the following reaction scheme ha 1 o- ( CH2 ) base VIII (cH2)n-z—y-Ri wherein n, R, Rx and Z are as hereinabove defined and halo is a reactive halogen, such as bromine, chlorine or i od i ne .

Compounds of Formula VIM are commercially available 15 or may be prepared by methods we 11 known in the art.

Compounds of Formula VIII wherein Z Is C=0 may, for example, be prepared by reacting the appropriate w-ha 1oa1kanoy1 halide and a (substituted)benzene in the presence of a Lewis acid, such as aluminum chloride, or by reacting a 20 (4-substituted)pheny1 Grignard reagent with an appropriate uj-ha 1 oa 1 ky 1 n i t r i 1 e . Compounds of Formula VIII wherein Z is CHOH may be prepared by reduction by means of chemical reducing agents or catalytic hydrogenation of the corresponding 1-(4-subst i tuted)pheny 1 -ui-ha 1 oa 1 kanones of Formula 11 -Z&- -miojiT 19424 8 VI It prepared as described above or by reaction of a (4-substituted)phenyl Grignard reagent with an appropriate uj-ha loal kanaldehyde. 3-(4-Naphthaienyloxy-1-pi per? dyl)-1-pheny1propanones, 5 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-a1dehyde. 4-(Naphthy1eny1oxy)-1-piperidinea1kanols 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 Ml may, 15 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 atmospheres of pressure and room temperature, that is about 20 20°-25°C, in the presence of a suitable catalyst, such as platinum, platinum oxide or rhodium, until one equivalent of hydrogen is consumed.

A 1ternative1y, 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 l/2 to 8 hours at a temperature of from 0°C to the reflux temperature of a lower aliphatic alcohol 30 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. 35 Compounds of Formula I prepared in the form of free bases may be converted to their acid addition salts by reaction with a pharmaceutica11y acceptable acid.

•H-ttjr \% D9424 3 -yf- The optical isomers of optically active compounds of Formula I may be separated by means of any suitable resolving agent. For example, the optical isomers of compounds of Formula I wherein Z is hydroxymethylene may be sepa-5 rated by using a (+)- or (-)-binaphthy1 phosphoric 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.

EXAMPLE 1 4-(2-Naphtha1enyloxy)-1-(pheny1methyl)piperidine hydrochloride To a stirred suspension of 1.80 g (37-5 mmole) of pen-tane washed 50$ sodium hydride dispersion in 50 ml of dry dimethy1formamide under argon is added a solution of 4.75 g (25.0 mmole) of 1-phenylmethy1-4-piperidinol in 20 ml of 15 dry dimethy1formamide followed by a solution of 3-83 g (26.2 mmole, 1.05 eq.) of 2-f1uoronaphthalene in 20 ml of dimethylformamide. The mixture is heated at 75°C for 23 hours, cooled, poured into ice water and extracted twice with ether. The extracts are washed with water and brine, 20 dried over magnesium sulfate and filtered. The filtrate is treated with HCl/methanol and the resulting 4-(2-naphtha1eny1oxy)-1-(pheny1methy1)p i per i di ne hydroch1 or i de recrystal1ized from butanone/methanol. M.P. 242-244°C.

EXAMPLE 2 4-(1-Naphtha 1eny1oxy)-l-phenylmethylpiperidi ne hydroch1 or i de When in the procedure of Example 1, 1-fluoronaphthalene is substituted for 2-f1uoronaphthalene, 4-(l-naphthalenyloxy)-l-(phenylmethyl)piperidine hydroch1 or ide is produced. M.P. 222-224°C. 30 EXAMPLE 3 4-(5-Methoxy-1-naphthalenyloxy)-l-(phenylmethyl)piperldine hydroch1 or i de When in the procedure of Example 1, 5-methoxy-l-f1uoronaphtha1ene is substituted for 2-f1uoronaphthalene, 4-(5-methoxy-l-naphtha 1eny1oxy)-l-(phenylmethyl)piperidine 35 hydrochloride is produced. ' 1)'942 4 8 EXAMPLE 4 4-(1-Methyl-2-naphtha 1eny1oxy)-l-methylpiperidine hydroch 1 or i de When in the procedures of Example 1, 1-methyl-2-f1uoronaphthalene is substituted for 2-f1uoronaphtha1ene 5 and 1-methyl-4-piperidino! is substituted for 1-phenyl-methy1 -4-p i pe r i d i nol, 4-(1-methyl-2-naphthaleny1oxy)-l-methy1piperidine hydrochloride is produced.

EXAMPLE 5 4-(4-Tr1f1uoromethy1-2-naphthalenyloxy)-l-methylpi perid?nol hydroch1 or i de When in the procedure of Example 1, 4-trif1uoromethy1 - 2-fluoronaphtha1ene is substituted for 2-f1uoronaphtha1ene and 1-methyl-4-piperidinol is substituted for 1-phenyl- methyl-4-piperidinol, 4-(4-tri fluoromet hy1-2-naphthalenyl- oxy)-1-methylpi per idine hydrochloride is produced.

EXAMPLE 6 4-(5-Fluoro-l-naphthalenyloxy)-l-ethylpiperidine hyd ro-ch1 or i de When in the procedure of Example 1, 1,5~dif1uoronaphthalene is substituted for 2-fluoronaphtha1ene and 1-ethy1-4-piperidinol is substituted for 1-phenylmethy1-4-20 piperidinol, 4-(5-f1uoro-1-naphtha 1eny1oxy)-1-ethy1piperi-dine hydrochloride is produced.

EXAMPLE 7 4-(2-Naphtha 1eny1oxy)p i per i d i ne hyd roch1 or i de To a stirred solution of 64.6 g (0.204 mole) of 4-25 (2-naphthalenyloxy)-1-phenylmethylpiperidine in 500 ml of methylene chloride is added 37.0 ml (.268 mole) of 2,2,2-trichloroethyl ch1oroformate and about 200 mg . of potassium carbonate. The mixture is stirred at room temperature for 48 hours and poured into a volume of 30 ether and water. The organic phase is washed with dilute hydrochloric acid and aqueous potassium carbonate, dried over magnesium sulfate, and concentrated _i_n vacuo.

The resulting l-(2,2,2-trich1oroethoxycarbony1)-4-(2-naphtha 1eny1oxy)piperidine is dissolved in a mixture 35 of 250 ml of acetic acid, 250 ml of tetrahydrofuran and M-IQ^ oo '94248 -yt- 125 ml of water. 28.5 g (.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 filtered and the solvents are removed i n vacuo. The residue 5 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-10 tion washed, dried over magnesium sulfate and concentrated i n vacuo to yield 4-(2-naphtha 1eny1oxy)piperidine, which is redissolved in ethanol/ether and treated with dry HC1, and the hydrochloride salt recrystal1ized from butanone/ methanol. M.P. 229-5-231-5°C. 15 EXAMPLE 8 4-(l-Naphthalenyloxy)piperidine hydrochloride When in the proceudre of Example J, 4-(1-naphtha -1eny1oxy)-1-phenylmethy1)piperidine is substituted for 4-(2-naphthalenyloxy)-l-phenylmethyl)piperidine, 4-(1-20 naphtha 1eny1oxy)piperidine hydrochloride is produced.

EXAMPLE 9 4-(4-T r i fIuorome thyl-2-naphthalenyloxy)piperidine hydroch lor i de When in the procedure of Example J, 4-(4-trifluoromethy 1-2-naphtha1eny1oxy)-1-methy1piperidine is substi-25 tuted for 4-(2-naphthalenyloxy-l-(phenylmethy1)-piper- idine, 4-(4-1 r i f1uoromethyl-2-naphthalenyloxy)piperidine hydrochloride is produced.

EXAMPLE 10 4-(5-F1uoro-1-naphthalenyloxy)p i per i d i ne hyd roch1 or i de 30 When in the procedure of Example 7, 4-(5-f1uoro-1- naphthaleny1oxy)-1-ethy1piperidine is substituted for 4-(2-naphthalenyloxy)-l-(phenylmethyl)piperidine, 4-(5-f1uoro-1-naphtha1eny1oxy)piperidine is produced. #. 194 2 4" EXAMPLE 11 4-(5-Methoxy-1-naphtha 1eny1oxy)pi per id i ne hydroch1 or i de A solution of 18.4 g (50 mmole) of 4-(5-methoxy-l-naphtha1eny1oxy)-1-(phenylmethy1)piperidine in 10 ml 5 of 1,2-dich1oroethane is added gradually to a chilled solution of 65 mmole of vinyl ch1oroformate in 50 ml of 1,2-dich1oroethane and the mixture stirred at room temperature for 4 hours and concentrated in vacuo.

The thus obtained 4-(5-methoxy-1-naphtha1eny1oxy)-10 1-(viny1oxycarbony1)piperidine is stirred for 2 hours with 2N HC1 in methanol to yield 4-(5-methoxy-l-naph-thalenyloxy)piperidine hydrochloride.

EXAMPLE 12 4-(1-Methy1-2-naphtha 1eny1oxy)piperidine hydrochloride 15 When in the procedure of Example 11 4-(1-methy1-2- naphtha1eny1oxy)-1-methy1piperidine is reacted with benzyl chloroformate, the resulting 4-(1-methy1-2-naph-tha 1eny1oxy)-l-(phenylmethoxycarbonyl)piperidine yields upon hydrolysis 4-(1-methy1-2 - naphtha 1eny1oxy)piperidine 20 hydrochloride.

EXAMPLE 13 4-f4-(2-Naphthaleny1oxy)-l-piperidyl]-l-pheny1-l-butanone hydroch1 or i de A solution of 5-67 9 (25 mmoles) of 4-(2-naphtha-1 eny 1 oxy) p i per i d i ne, 5-0 g (27.4 mmole) of 4-chloro-l-25 pheny1-1-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 MgS04. 30 A solution of an excess of HC1 in ether is added and the resulting precipitate recrystal1ized from methanol/ butanone to yield 4-(2-naphtha1eny1oxy-l-piperidy1)-1-pheny1-1-butanone hydrochloride.

■M -loyir- EXAMPLE 14 19424 4-r4-(2-Naphthalenyloxy)-1-piperi dyl1-l-(4-f1uoropheny1)-1-butanone hydrochloride When in the procedure of Example 13, 4-ch1oro-1-(4- f1uoropheny1)-1-butanone is substituted for 4-chloro-l- pheny1 -1-butanone; 4-[4-(2-naphtha1eny1oxy)-1-piperidy1]- l-(4-f1uorophenyl)-1-butanone hydrochloride is produced.

M.P. 219-221.5°C .

EXAMPLE 15 4-r4-(l-Naphthalenyloxy)-l-piperidyll-l-(4-fluorophenyl)-1-butanone hydrochlor i de When in the procedure of Example 13, 4-chloro-l-(4- f1uoropheny1)-1-butanone is substituted for 4-chloro-l- pheny1 -1-butanone and 4-(1-naphthaleny1oxy)piperidine hydrochloride is substituted for 4-(2 - naphtha 1eny1oxy)- piperidine hydrochloride, 4-[4-(1-naphtha 1eny1oxy)-1- piperidyl]-1-(4-f1uoropheny1)-1-butanone hydrochloride is produced. M.P. 220-222.5°C.

EXAMPLE 16 3-f 4-(5-Methoxy-1-naphthalenyloxy)-l-piperidyl]-1-(4-chlorophenyl)-1-propanone hydrochloride When in the procedure of Example 13, 4-(5-methoxy-1- naphtha 1eny1oxy)piperidine hydrochloride is substituted for 4-(2-naphtha 1 enyloxy)pi peridine hydrochloride and J>- ch1oro-1-(4-ch1oropheny1)-1-propanone substituted for 4- chloro-l-phenyl-1-butanone, 3"[^-(5-methoxy-l-naphthalenyl ■ oxy)-l-piperidyl]-l-(4-chlorophenyl)-1-propanone hyd ro- chloride is produced.

EXAMPLE 17 -f4-(2-Naphtha 1eny1oxy)-l-piperidyl"l-l-(4-methy1phenyl)-1-pentanone hydrochloride When in the procedure of Example 13, 5-ch1oro-1-(4- methylpheny1)-1-pentanone is substituted for 4-chloro- 1-phenyl-1-butanone, 5~[4-(2-naphtha1eny1oxy-1-piperidy1]- l-(4-methylphenyl)-l-pentanone hydrochloride is produced. 13 -pg-EXAMPLE 18 ^ K-1031" 19424 8 4 - f 4- (1-Methvl -2-naphtha 1 enyl oxy )-l-piperidyll-l-(4-f1uorophenyl)-l-butanone A solution of 3.^7 g (12.5 mmole) of 4-(l-methyl- 2-naphtha 1enyloxy)pI per idine , 2.63 g (13•1 mmole) of 4-chloro-l-(4-f1uorophenyl)-1-butanone, 5-2 g (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 sulfate, and concentrated j_n vacuo to yield 4-[4-(1-methy1-2-naphthalenyloxy)-1-piperidyl]-1- (4-f1uoropheny1)-1-butanone .

EXAMPLE 19 6-[4-(4-Trifl uoromethy 1 - 2- naphtha 1 eny 1 oxy )-l-piperidyl~j- 1-[4-methoxypheny1)-1-hexanone When in the procedure of Example 18, 4-(4-trifluoro methy 1-2-naphtha1eny1oxy)piperidine is substituted for 4-(1-methy1-2-naphtha 1eny1oxy)piperidine and 6-bromo-1-(4-methoxypheny1)-1-hexanone substituted for 4-chloro-1-(4-f1uorophenyl)-1-butanone, 6-[4-(4-1rif1uoromethy1 -20 2-naphthalenyloxy)-l-piperidyl]-l-(4-methoxypheny1)-1-hexanone is obtained.

EXAMPLE 20 g-(4-F1uoropheny1)-4-(l-methyl-2-naphtha lenyl oxy) -1-pi per i di nebutanol When in the procedure of Example 18, 4-chloro-l- (4-f1uoropheny1)butanol substituted for 4-chloro-l-(4- fluorophenyl)-l-butanone, a-(4-f1uorophenyl)-4-(l-methyl- 2-naphtha 1eny1oxy)-1-piperidinebutanol is produced.

EXAMPLE 21 g-Phenyl-4-(5~fluoro-1-naphtha1enyloxy)-l-piperidine-propanol When in the procedure of Example 18, 4-(5-f1uoro-1- naphthalenyloxy)piperidine is substituted for (l-methyl-2-naphtha 1eny1oxy)piperidine and 3-bromo-1-pheny1 -propanol substituted for 4-chloro-1-(4-f1uoropheny1)-1-butanone, a-phenyl-4-(5-fluoro-l-naphthalenyloxy)-1-35 pi per idinepropanol is obtained. ^ 194248 EXAMPLE 22 3- f4- ( 5-Met hoxy-1 -naph tha lenyl oxy )-l-piperidyl "] -1- ( 4-fluorophenyl)-1-propanone A mixture of 25-5 g (0.1 mole) of 4-(5-methoxy-1-naphtha1eny1oxy)piperidine, 9 g (0.3 mole) of paraform-5 aldehyde and 13.8 g (0.1 mole) of 4'-f1uoroacetophenone 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 10 recrystal1ized from ethanol to give 3-[4-(5-methy1-1- naphthalenyloxy)piperidyl-l-(4-fluorophenyl)-1-propanone.

EXAMPLE 23 g-(4-F1uorophenyl)-4-(2-naphthalenvloxy)-l-piperidinebutanol To 8.0 g (0.02 mole) of 4-[4-(2-naphtha 1eny1oxy)-15 1-piperidy1]-1-(4-f1uoropheny1)-1-butanone HC1 in 50 ml of methanol is added 1.1 g (0.02 mole) of sodium methoxide and then 2.7 g (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 20 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 phase, 25 washed with water and with brine, dried over MgS04, filtered and concentrated to a solid. The solid material is recrysta11ized from ethanol/water to give g-(4-fluoro-phenyl)-4-(2-naphthalenyloxy)-l-piperidinebutanol.

EXAMPLE 24 g-(4-Methoxypheny1)-4-(4-tri fluoromethy1-2-naphthalenyl-oxy) -1-p i per id inehexano1 When in the procedure of Example 23, 6-[4-(4-tri-f1uoromethy1-2-naphtha1enyloxy)-1-p i per i dy1]-1-(4-methoxypheny 1 )-1-hexanone hydrochloride is substituted for 4-[4-(2-naphthalenyloxy)-l-piperidyl]-1-(4-f1uoropheny1)-1- -jk- 194248 butanone, a-(4-methoxypheny1)-4-(4-1r i f1uoromethy1-1-naphtha1eny1oxy)-1-piperIdinehexano1 is obtained.

EXAMPLE 25 Tablet Formulation 5 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]-l-(4-fluoropheny1)- 1-butanone hydrochloride (b) Wheat starch 3-5 rng 10 (c) Lactose 10.0 mg (d) Magnesium stearate 0.5 rng 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. 15 The mixture is compressed into tablets weighing 39*0 mg each.

EXAMPLE 26 Gelatin Capsule Formulation An illustrative composition for hard gelatin capsules 20 i s as foilows: Mg (a) 4-[4-{2-naphtha1eny1oxy)-1- 10 piperidyl]-l-(4-fluoropheny1)-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 capsules at a net fill of 115 mg per capsules.

EXAMPLE 27 30 Injectable Suspension Formulation An illustrative composition for an injectable suspension is the following 1 ml ampul for an intramuscu1 ar i nj ect i on.

Claims (1)

1. ■M 10 yr % 1942 4s Weight Percent (a) 4-[4-(2-naphthalenyloxy)-1-piperidyl]-l-(4-fluorophenyl)-1-butanone (particle size <10^) 1.0 ( b) Polyvinylpyrrolidone (M.W. 25000) 0.5 (c) Lec i th i n 0 .25 (d) Water for injection to make 100 .0 The materials (a)-(d) are mixed, homogeni ized, and filled into 1 ml ampules which are sealed and autoclaved 20 minutes at 121°C . Each ampul contains 10 mg per ml of novel compound (a). <2-1 -s*r-;\NHAT/WE claiia Bi;' ■G'LA-I M3;1. A compound of the formula;(CH2 ) n~Z—\ VRi;3 wherein n is an integer of from 2 to 5; R is selected;4 from hydrogen, halogen, straight or branched chain alkyl;5 of from 1 to 4 carbon atoms, straight or branched chain;6 alkoxy of from 1 to 4 carbon atoms and trif1uoromethy1;;7 Ri is selected from hydrogen, halogen, straight or;8 branched alkyl of from 1 to 4 carbon atoms, and straight;9 or branched alkoxy of from 1 to 4 carbon atoms; and Z is;10 selected from carbonyl and hydroxymethy 1ene; an individual;11 optical isomer, or a pharmaceutica11y acceptable acid;12 addition salt thereof.;1 2. A compound of claim 1 wherein Z is carbonyl.;1 3. A compound of claim 1 wherein n is 3-;1 4. A compound of claim 1 wherein Ri is halogen.;1 5. A compound of claim 4 wherein Ri is fluorine.;1 6. A compound of claim 1 wherein R is selected from;2 hydrogen and halogen.;1 7. A compound of claim 1 which is 4-[4-(2-naphtha-;2 1eny1oxy)-1-piperidy1 J-1-(4-fluoropheny1)-1-butanone or a;3 pharmaceutica11y acceptable acid addition salt thereof.;194248;-28-;8. A compound of claim 1 which is 4-]4-(1-naphtha-lenyloxy) -1-piperidyl] -1- (4-flourophenyl) -1-butanone or a pharmaceu£ically acceptable acid addition salt thereof.;9. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutical carrier.;10. An antipsychotic composition comprising an anti-psychotically effective amount of a compound of claim 1 and a pharmaceutical carrier.;11. A composition of claim 9 or claim 10 comprising from 0.2 to 200 mg of the compound in unit dosage form.;12. A compound of the formula;H.Z. PATE»iY OFF ;C£;-3 FEB 1984;RECEIVED;2;3;4;5;6;7;8;9;1;1;2;1;2;1;1;2;1;2;1;2;3;1;2;3;194248 M_1°51;r2;wherein 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 trifluoromethy1 and R2 is hydrogen, lower alkyl or phenyl(lower alkyl) wherein the lower alkyl group is a straight alkyl chain of from 1 to 3 carbon atoms, or an acid addition salt thereof.;13, A compound of claim "12 wherein R2 is hydrogen.;■2:4. A compound of claim "12 where in R2 is methyl or pheny1methy1.;!>>.. A compound of claim 12 wherein R is hydrogen or halogen.;16.. A compound of claim 12 wherein R is hydrogen.;3_7. A compound of claim 12 which is 4-(2-naphtha-leny1oxy)pI peridine or an acid addition salt thereof.;18. A compound of claim 12 which is 4-(1-naphtha-leny1oxy)piperidine or an acid addition salt thereof.;.19. A compound of claim 12 which is 4-(2-naphtha-1enyloxy)-1-(phenylmethy1)piperidine or an acid addition salt thereof.;_2Q„ A compound of claim 12 which is 4-(1- naphtha-lenyloxy)-1-(phenylmethy1)pi per idine or an acid addition salt thereof.;r-:;-;. r,",TC:'J7 OFFICE;-3FEB1984;RECEIVED;1;2;3;4;5;6;7;8;9;10;11;12;13;14;15;16;17;1;2;3;4;5;M 1031-;194248;-30-;21i. A process for the preparation of a compound of;(;claim 1 which comprises a) alkylating a compound of the formula;R-t I;o;H;or an acid add i t i on sa 11 thereof w i th a compound of the formula halo-(CH2)n-Z-^^-R1;wherein halo is CI, Br or I, and n, R, Ri and Z 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 potassium iodide for from 24 to 96 hours at a temperature of from -about 20° to i<180OC, or i b) when Z is hydroxymethy1ene, reducing a compound of claim 1 wherein Z is carbonyl, and c) when a pharmaceutica11y acceptable salt is desired, reacting the thus obtained compound with a pharmaceutica11y acceptable acid.;22 I;-24J. A process for the preparation of a compound of claim 12 which comprises a) reacting a 4-piper idinol salt of formula;0"M+;0;1;r3;wherein M+ is an alkali metal cation and Rs is lower alkyl;-3FEB1984;Rprpiv/cn;•» /t ■ N -;194248;-31-;6 or phenyl(lower alkyl) with a naphthalene fluoride of;7 formula;8;9 wherein R has the meaning defined in claim -£6""in the pre-sence of a polar aprotic solvent at a temperature of from;11 50°C to the boiling temperature of the solvent for from;12 ■ l to 24 hours; •;1J> b) when R2 is hydrogen, refluxing the thus;Ik obtained compound wherein R2 is lower alkyl or phenyl-;15 (lower alkyl) in the presence of an aprotic solvent and;16 a trace of an acid scavenger With a chloroformic acid;17 ester to yield a carbamate derivative and cleaving the;18 carbamate by hydrolysis or reduction; and;19 c) when a salt is desired, reacting the compound;20 thus obtained with a suitable acid.;I;1 23. A process of claim 22wherein the chloroformic;2 acid ester is 2,2,2-trichloroethyl ch1oroformate.;1;24j. A compound as claimed in any one of claims 1 to 2(l> substantially as hereinbefore described with reference to any example thereof.;25, A process as claimed in either of claims 21 and 22;?when performed substantially as hereinbefore described.;J. P. & \*U- . ■ 26. A product as claimed in claim-Hi" when prepared by a process as claimed in claim 22, 23 or 25. j ! i uATCD THIS DAY OF tr€U< A. J. PARK & SON AGSNTS fOi TH£ APHJCAHTO. w.z. patent office -3FEB 1984 RECEIVED