IE49998B1 - 4-(naphthalenyloxy)piperidine derivatives - Google Patents

Abstract

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 hydroxymethylene 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 or their salts wherein R has the meanings defined above and R2 is hydrogen, lower alkyl or phenyl(lower alkyl).

Description

This invention relates to novel derivatives of 4-( naphthalenyloxy)piperidines and methods for their preparation. More particularly it relates to new 4-naphthaleny1oxypiper idines, useful as chemical intermediates, and their N-(m-benzoy1alkyl) and N-(^-hydroxy-^-phenylalkyl) derivatives, useful as neuroleptic tranquilizers whose use does not induce significant extrapyramidal side effects. 1-Phenyl-&·-(1-p iper idy 1 )a 1 kanones constitute an important class of central nervous system depressants. Various compounds of this class are claimed, for example, in U.S.

Patent Specification Nos. 3,438;991; 3,518,276; 3,576,810; 3,816,433; 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 extra25 pyramidal side effects and transient hypotension.

It has now been discovered that the novel naphtha1enyloxy-l-piperidy1)-1-phenylalkanones and the corresponding naphthalenyloxy-n-pheny1 -1-piperidinaIkanols of this invention display potent antipsychotic activity without inducing significant extrapyramidal side effects and with little effect on blood pressure.

Novel compounds according to the present invention, which have utility as anti - psychotic agents are of formula I R ''N/ OR1 (including the individual optical isomers thereof) wherein n is an integer of from 2 to 5; R is hydrogen, alkyl, alkoxy, halogen or trifluormethyl; R^ is hydrogen, alkyl, alkoxy or halogen; and Z is carbonyl or hydroxymethylene; and the pharmaceutically acceptable acid addition salts thereof.

Compounds of Formula I include 0)-/4-(1- and 2-naphthalenyloxy-l-piperidyl )/-1-(4-substituted)pheny1-1-alkanones and 4-(1- and 2-naphthalenyloxy)-a-(4-substituted)phenyl-1piperidinealkanols their individual optical isomers, and their pharmaceutically 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. 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 examples of alkoxy groups are methoxy, ethoxy and isopropoxy. 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 occupied by the (4-piperidyloxy) 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.

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 ph tha 1 eny 1 oxy) -1- p i per i dy 1 ] -1- ( 4- f 1 uorophenyl) 1-butanone, 4-(4-( 2-na ph t ha 1 eny loxy)-1-pi per idyl )-1-( 4- fluorophenyl) 1-butanone, 4-(4-(6-chloro-2-naphtha1 enyloxy)-l-piperidyl)-l-( 4-f,uorophenyl )-1-butanone, 3- (4-(5-methoxy-1-naphtha 1enyloxy)-1-pi per idyl )-1-(415 chlorophenyl)-l-propanone, 4- (4-(2-naphtha 1enyloxy)-1-pi per idyl )-1-(4-methylphenyl )1-butanone, - (4-(1-methy1-2-naphtha IenyIoxy)-1-piper idyl )-1-(4-ethoxyphenyl)-l-pentanone, 4-(4-(8-methoxy-2-naphtha 1enyloxy)-1-pi per idyl)-1-pheny1 1-butanone, 6- i4-(5-fluoro-1-naphthalenyloxy)-1-piperidyl )-1-(4-fluoropheny, )-1-hexanone, 4-(4-(2-tr i f,uoromethyl-1-naphtha 1enyloxy)-1- pi per id i ny1]25 1-(4-bromophenyl)-1-butanone, 4-(1-naphthalenyloxy)-a-(4-fluorophenyl)-1-pi per id inebutanol, 4-(2-naphtha,eny,oxy)-a-(4-fluorophenyl)-1-piper id inebutanol , 4-<4-tr i f1uoromethyl-2-naphtha 1enyloxy)-a-phenyl-1-pi per ιό inebutanol, 4-(6-bromo-2-naphthalenyloxy)-a-(4-bromophenyl)-1-pi per id i nepropanol, 4-(7-isopropy1-1-naphthalenylcxy)-a-(4-fluoropheny1)-135 ρiperidinepentanol, 4-(3-ethoxy-2-naphtha 1enyloxy)-a-(4-methoxyphenyl)-1p i per id inebutanol, '49998 4-(2-naphthalenyloxy-a-(4-ethy1 phenyl )-1-pi per id inehexanol, 4-(8-fluoro-1-naphthalenyloxy)-a-(4-fluorophenyl)-1piper id inebutanol, and 4- (2-methy 1-1-naphtha leny loxy )-0.-( phenyl) -1-pi per idi nebutanol.

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-aminobenzo ic, 4-hydroxybenzoic, anthranilic, cinnamic, salicylic, aminosalicylic, 2phenoxybenzoic, 2-acetoxybenzoic and mandelic acids; and sulfonic acids, such as methanesulfonic, 2-hydroxyethanesul fonic and jj-toluenesul fonic acids.

Novel intermediates for the preparation of compounds of Formula I are compounds of Formula II R2 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 Rg is hydrogen, methyl or phenylmethyl and those wherein R is hydrogen or halogen.

Exemplary compounds of Formula II include: 4-(1-naphtha 1enyloxy)p i per i d i ne, 4- (2- naphtha 1 eny 1 oxy) p i per i d i ne, 4-(6-chloro-2-naphthalenyloxy)pi per id ine, 48888 4- (5-methox y-1 - na ph t ha 1 en y 1 ox y) p i per i d i ne, 4-(1-methyl-2-naphthalenyloxy)pi per idine, 4-(8-methoxy-2-naphthalenyloxy)pi peridine, 4-(5-fluoro-1-naphtha 1enyloxy)pi per idine, 4-(2-tr ifluoromethyl-1-naphtha 1enyloxy)pi per idi ne, 4-(6-bromo-2-naphthalenyioxy)pi per id ine, 4-(7- isopropyl-1-naphthalenyioxy)pi peridi ne, 4- ( 4- tr i fluoromethyl-2-naphtha 1 enyioxy) p i per i d i ne, 4-(3-ethoxy-2-naphthalenyloxy)pi per idine, 4-(8-fluoro-1-naphthalenyloxy)pi per id ine, 4-(2-methyl-1-naphthalenyloxy)pi per id ine 1-methy1-4-(1-naphthalenyloxy)piper id ine, 1-methyl-4-(6-chloro-2-naphthalenyloxy)pi per id ine, 1-methy1-4-(1-methyI-2-naphtha1enyloxy)pi per idine, 1-methyl-4-(4-tr i fluoromethyl-2-naphthalenyloxy)piper id ine 1-ethyI-4-(5-fluoro-1-naphtha!enyioxy)pi per idine, 1-methy1-4-(7-i sopropyl-1-naphtha 1enyloxy) pi per id ine, 1-propyl-4-(8-methoxy-2-naphtha!enyioxy)pi per Id ine, 1-(phenylmethyl)-4-(2-naphthalenyloxy)pi per idi ne, 1-(2-phenylethyl)-4-(5-methoxy-1-naphthalenyloxy)pi perid i ne, 1-(phenylmethyl)-4-(2-tr ifluoromethyl-1-naphtha 1enyioxy)piper idine, 1- ( pheny lmethyl )-4- (6-bromo-2-naphtha leny loxy.) pi per i d i ne, 1-(phenylmethyl)-4-(5-ethoxy-2-naphthalenyloxy)piper idine, 1-(3-phenyl propyl)-4-(8-fluoro-1-naphthalenyloxy)piperidine, and their acid addition salts.

The novel compounds of Formula 1 are antipsychotic agents useful when administered alone or in the form of pharmaceutical preparations containing the novel compounds in combination with a pharmaceutical carrier as neuroleptic tranquilizers in warm blooded animals. Neuroleptic tranquilizers 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, indue· ing a state of general quiescence in the patient without inducing sleep. Patients suitable for treatment with 49Q98 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.

Pharmaceutical compositions containing compounds of Formula 1 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 subcutaneously, 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 patient 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 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; disintegrating agents, such as corn starch, guar gum or alginic acid; lubricants, such as stearic acid or magnesium 9 9 9 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 sterile liquid, such as an oil, water, an alcohol or mixtures thereof, with or without the addition of a pharmaceu ticaliy suitable surfactant, suspending agent, or emulsify ing 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 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 formula20 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 suitably contain suspending agents, such as pectin, carbomers, methy, cellulose, hydroxypropy1 cellulose or carboxymethy, cellulose, as well as buffers and preservatives.

Illustratively, when 4-[4-(2-naphthalenyloxy)-lp i peri dy1]-1-(4-f1uoropheny1)-1-butanone hydrochlor ide was administered intraperitoneally to mice at a dosage of 0 .06 mg/kg the aggregate toxicity of ^-amphetamine was inhibited in 5θί of the mice tested according to the procedures disclosed by J. Burn et al., Arch. I nt. Pharmacodyn. 115, 290-5 (1955), thus demonstrating antipsychotic effectiveness, whereas a dosage level of 0.98 mg/kg of the known tranquilizer chlorpromazine is required to attain a similar level of response. Similarly, compounds of this invention evince neuroleptic activity - 48988 through the inhibition of pernicious preening in mice tested according to the method disclosed by A. Kandel et al., Fed. Proc., 19 (1, Pt. l), 24 ¢1960).

The neuroleptic potency of these compounds is accompanied by a reduced tendency to produce extrapyramidal side effects in patients treated with 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-naphtha1enyloxy)-1-piperidyI)-1-(4-f1uoropheny1)-1-butanone hydrochloride was administered intraperitoneally to mice, a dosage of J4.0 mg/kg was required to counteract the behavioral effects of apomorphine in 50$ of the mice tested according to the genera] method disclosed by P. A. J. Janssen et al., in Arzneim-Forsch. 10, 1003 (i960), whereas only 1.4 mg/kg of chlorpromazine was required to attain a similar effect.

Compounds of Formula I are prepared by alkylation of intermediate compounds of Formula lla, H which represent compounds of Formula II wherein Ra is hydrogen and R has the above-identified meaning. Compounds of Formula lla are themselves prepared by dealkylation or debenzylation of compounds of Formula I lb, I J IIb I Ra wherein R3 is lower alkyl or pheny1(lower alkyl) and R has the above-defined meaning, which represent compounds of Formula II wherein Ra is lower alkyl or phenyl(lower alkyl). It is thus apparent that all of the compounds of Formula II are useful intermediates for the pharmaceu tically useful compounds of Formula I.

Compounds of Formula lib are prepared by reaction of an N-substituted-4-ρiperidinol salt of Formula V 0M+ N' I Rs wherein R3 is lower alkyl or phenyl(lower alkyl) and MT is an alkali metal cation, such as potassium, sodium or lithium, with a naphthalene fluoride of Formula VI RF VI 48998 wherein R has the meaning defined above, to produce a l-(lowar alkyl) or l-phenyl(lower alkyl)-4-naphthalenyloxypiperidine of Formula 11b. The compounds of Formula 1 la, wherein Ra is hydrogen, are prepared by dealkylation of N-substituted compounds of Formula Ub by means of a chloro0 II formic acid ester of Formula R4OC-C1, wherein R4 is 2,2,2trichloroethyl, vinyl, substituted vinyl, benzyl, substituted benzy, or cycloalkyl, which is reacted with the compound of Formula lib in the presence of a proton scavenger, to produce a l-(R4-oxycarbony1)-4-(naphthanlenyloxy)piperidine of Formula VI I VII o=c-o-r4 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. 9998 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 W. Adcock et al., in J. Am. Chem. Soc. 8g(2), 386-390 (1967) and in J. Am. Chem. Soc, 58(7), 1701-1711 (1976). ίο Piperidinol salts of Formula V are prepared by reacting the corresponding 1-lower alkyl- or 1-phenyl(loweral kyl)-4-pi per i di nol with a strong base, such as an alkali metal hydride, an alkali metal amide or alkyl lithium according to generally known procedures. The piperidino! 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 about 24 hours. Suitable solvents include tetrahydrofuran, dimethoxyethane, diglyme, dioxane, hexamethylphosphorus triamide, dimethylacetamide, dimethylsulfoxide, 1-methyi2-pyrrolidone, sulfolane and, especial 1y, dimethy1 formamide.

The reaction is quenched and the resulting N-substituted 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 recrystallization and dried. Suitable solvents for recrystallization are, for example, lower aliphatic alcohols, such as methanol, ethanol and isopropanol; ketones, such as acetone and butanone; esters, such as ethyl acetate; hydrocarbons, such as hexane; and combinations thereof.

The thus prepared 1-lower alkyl- or l-pheny1(loweral ky1)-^-( naphthalenyloxy)piperidine of Formula lib 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 l-unsubstituted-4-(naphthalenyloxy)oiperidine of Formula Ila. Suitable chloroformic acid esters are those which yield R4-oxycarbonyl 48998 substituents which may be cleaved from the nitrogen atom of the compound of Formula Vll hydrolytically or by reducing 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 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 cycloalkyl esters, such as the cyclohexyl, cyclopentyl, adamantyl 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 trifluoroacetic acid, in suitable solvents. Chloroformic acid esters suitable for displacing alkyl and benzyl substituents 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 Peptide Synthes i s, 2nd Edition (John Wiley & Sons) p. 2157 (I976) and by R. Olofson et al. in 1J.S . patent 5,9Ο5,9θ1, which are hereby incorporated by reference.

The preferred chloroformic acid ester for the dealkylation of compounds of Formula II wherein R£ 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 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, 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, 15-5$ by weight of the amount of the compound of Formula lib, of a proton scavenger, which may be an inorganic base, such as sodium or potassium carbonate, a strong organic base, such as triethylamine, or a mixture thereof. The reaction mixture is maintained at a temperature between about 0°C and the reflux temperature of the solvent for from 1 to 96 hours. The thus obtained l-(Rj-oxycarbonyl)4-(naphthalenyloxy)piperidine of Formula VI i is isolated, for example, by extraction into an organic solvent and evaporation of the solvent, according 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-phenyl(lower alkyl)-substituted compound of Formula lib 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 ehloroformate in the presence of a trace amount of a proton scavenger for from 6 to 24 hours at a temperature of from 15° to 40°C, preferably at room temperature. The product is extracted into ether, washed with dilute acid and concentrated i n vacuo. The resulting 1-(2,2,2- tri chloroethoxycarbony 1)-4-( naphthaleny20 ,oxy)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, preferabl 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 1 to 6 hours until gas evolution ceases.

The solvents are evaporated and the N-unsubstituted com30 pound of Formula Ila 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 rebasification . The N-unsubstituted compound is recrystallized by conventional methods, preferably in the form of its acid addition salt, from suitable solvents, 49898 such as lower aliphatic alcohols, ketones, esters and combinations thereof.

Free bases of Formula I I prepared by the above-mentioned 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 hydrogen with a small excess of an uj-haloalkyl phenyl ketone or an 'u-halo-l-phenyl-l-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 derivative of Formula II 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 lla 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 l80°C 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 alcohols, 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 filtered and the solvent removed, isolating the product. Alternately, the filtrate may be treated with an ethereal solution of a suitable mineral or organic acid to give the corresponding salt of the product. The 49898 t crude product is filtered off, purified by recrystallization and dried. Suitable solvents for recrystallization are, for example, lower aliphatic alcohols, such as methanol, ethanol and isopropanol; ketones, such as acetone and butanone; nitriles, such as acetonitrile; and combinations thereof.

The general method for the preparation of the compounds of Formula I involves reacting a compound of Formula Ila, with a compound of Formula VIII halo-(CH_) —Z i n R VIII wherein, n, R, R^ and Z are as hereinabove defined and halo is a reactive halogen, such as bromine, chlorine or iodine.

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

Compounds of Formula VIII wherein Z is C=0 may, for example, be prepared by reacting the appropriate ω-haloalkanoyl halide and a (substituted)benzene in the presence of a Lewis acid, such as aluminum chloride, or by reacting a (4-substituted)phenyl Grignard reagent with an appropriate ω-haloalkylnitrile. 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-substituted)phenyl-io-haloalkanones of Formula Vlll prepared as described above or by reaction of a '4substituted)phenyl Grignard reagent with zn appropriate uu-ha loal kanal dehyde. 3- (4-Naphthalenyloxy-1-pi per idyl)-i-phenyIpropanones, 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 formaldehyde. 4- ( Naphthylenyloxy)-1-piper idinea1kanols 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 1 to 4 atomspheres of pressure and room temperature, that is about 20°-25°C, 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 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 fcr from about 1/2 to 8 hours at a temperature of from 0°C to the reflux temperature of a lower aliphatic alcohol solvent, such as methanol or ethanol, with a metal borohydride, such as sodium borohydride or potassium borohydride, to yield an alcohol cf 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.

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 sepa5 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 ai., in Tetrahedron Letters 1971 (48), pp. 4617-20.

EXAMPLE 1 4-(2-Naphtha 1eny1oxy)-1-(phenylmethyl)pi per idine Hydrochloride To a stirred suspension of 1.80 g (37-5 mmole) of pentane washed 5CT5 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-4-piperidinol in 20 m, of dry dimethylformamide 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, dried over magnesium sulfate and filtered. The filtrate is treated with HCl/methanol and the resulting 4-(2naphthalenyloxy)-1-(phenylmethyl)piperi dine hydroch1ori de recrystallized from butanone/methanol. M.P. 242-244°C.

EXAMPLE 2 4-( 1 -Naphthaienyloxy)-l-phenylmethylpiperidine Hydrochloride When in the procedure of Example 1, 1-f1uoronaphthalene is substituted for 2-f1uoronaphthalene, 4-(1naph tha 1 enyl oxy )-1-(, pheny Ime thy 1) pi peri di ne hydroch 1 or ide is produced. M.P. 222-224cC.

EXAMPLE 3 4-(5-Methoxy-l-naphthalenyloxy)-1-(phenylmethyl)pi per id i ne Hydrochlori de When in the procedure of Example 1, 5-methoxy-lfluoronaphthalene is substituted for 2-fiuoronaphthalene, 4-(5-methoxy-1-naphtha 1enyloxy)-1-(phenylmethyl)pi peri di ne hydrochloride is produced.

EXAMPLE 4 4-(1-Methy1-2-naphthalenyloxy)-l-methylpiperidine Hydrochi or ide When in the procedures of Example 1, l-methyl-2fluoronaphthalene is substituted for 2-fluoronaphthalene and l-methyl-4-piperidinol is substituted for 1-phenylmethyl-4-pi peri di nol, 4-(l-methyl-2-naphthalenyloxy)-1methylpiperidine hydrochloride is produced.

EXAMPLE 5 4-(4-Tr i fluoromethyl-2-naphthalenyloxy)-l-methylpi peri di nol Hydrochloride When in the procedure of Example 1, 4-trifluoromethy12-f1uoronaphthalene is substituted for 2-fluoronaphthalene and l-methyl-4-piperidinol is substituted for 1-phenylmethyl-4-piper id inol, 4-(4-tri fluoromethy1-2-naphthaleny1 oxy)-1-methy1 pi per idine hydrochloride is produced.

EXAMPLE 6 4-(5-Pluoro-1-naphthalenyloxy)-1-ethylp ioeridine Hydrochloride When in the procedure of Example 1, 1,5-difluoronaphthalene is substituted for 2-fluoronaphthalene and 1ethyl-4-piperidinol is substituted for l-phenyImethy1-4piper idinol, 4-(5-fluoro-1-naphthalenyloxy)-l-ethy1piperidine hydrochloride is produced.

EXAMPLE 7 4-(2-NaphthalenyloxyIpiperidine Hydrochloride To a stirred solution of 64.6 g (0.204 mole) of 4(2-naphthalenyloxy)-l-phenyImethy 1 pi peridine in 500 ml of methylene chloride is added 37.0 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 yacuo.

The resulting 1-(2,2,2-trichioroethoxycarbonyl)-4(2-naphthalenyloxy)piperidine is dissolved in a mixture of 250 ml of acetic acid, 250 ml of tetrahydrofuran anc 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 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 solu10 tion washed, dried over magnesium sulfate and concentrated i n vacuo to yield 4-(2-naphtha1eny1oxy)piper idine, which is redissolved in ethanoi/ether and treated with dry HC,. and the hydrochloride salt recrystallized from butanone/ methanol. M.P. 229.5*231-5'C.

EXAMPLE 8 4-(1-Naphthalenyloxy)p i per id i ne Hydrochi orΐde When in the proceudre of Example 7, 4-(1-naphthalenyloxy)-l-pheny1methyl)piperidine is substituted for 4-(2-naphthalenyloxy)-1-phenyImethyl)piperidine, 4-(l20 naphthaienyloxy)piperidine hydrochloride is produced. EXAMPLE 9 4-ί 4-T r i f1uoromethy 1-2-naphthalenyloxy)pi per id i ne Hydroch1 or i de When in the procedure of Example 7, 4-(4-trifluoromethyl -2-naphthalenyloxy)-l-methylpiperidine is substi25 tuted for 4-i2-naphthalenyloxy-l-(phenylmethyl)-piperi d i ne, 4-(4-1r i fIuoromethy t-2-naphthalenyloxy)p i per id ine hydrochloride is produced.

EXAMPLE 10 4-(5-71uoro-1-naphthalenyloxy)pi per id i ne Hydrochi or i de When in the procedure of Example 7, 4-(5-fluoro-lnaphthalenyloxy)-l-ethylpiperidine is substituted for 4-(2-naphthalenyIoxy)-1-(phenylmethyl)piperidine, 4i 5-f,uoro-1-naphtha 1eny1oxy)piperidine is produced. 48888 EXAMPLE 11 4-(5-Methoxy-1-naphthalenyloxyJ pi per id i ne Hydrochlor!de A solution of 18.4 g (50 mmole) of 4-(5-methoxy-lnaphthalenyloxy)-1-(phenyImethy1)piper idine in 10 mi of 1,2-dichloroethane is added gradually to a chilled solution of mmole of vinyl ehloroformate in 5θ 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-l-naphthalenyloxy)1-(vinyloxycarbony1)piper idine is stirred for 2 hours with 2N HCI in methanol to yield 4-(5_methoxy-l-naphtha 1eny1oxy)p i per1d i ne hydroch1 or i de.

EXAMPLE 12 4-(1-Methy1-2-naphthalenyloxy ipί peridina Hydroch1 oride When in the procedure of Example 11 4-(l-methy1-2naphthalenyloxy}-1-methylpiperidine is reacted with benzyl ehloroformate, the resulting 4-(l-methyl-2-naphthalenyloxy)-1-(phenylmethoxycarbonyl)piperidine yields upon hydrolysis 4-(l-methyl-2-naphthalenyloxy)piperidine hydrochloride.

EXAMPLE 15 4-1 4-(2-Naphthaleny1oxy j-l-piperidyll-l-phanyl-l-butanone Hydrochloride A solution of 5-67 g (25 mmoles) of 4-'2-naphthalenyloxy)pipsridine, 5-0 g (27.4 mmole) of 4-chloro-lphenyl-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 m, portions of methylene chloride, ether and water and the organic phase dried over MgSO4.

A solution of an excess of HCI in ether is added and the resulting precipitate recrystal Iized from methanol/ butanone to yield 4-(2-naphthalenyloxy-l-piperidyl)-1phenyl-1-butanone hydrochloride. 49988 EXAMPLE l4 4-(4-(2-Naphthalenyloxy)-1-piper idyl 1-1-(4-fluoropheny1) 1-butanone Hydrochloride When in the procedure of Example 13, 4-chloro-l-(4fluorophenyl)-l-butanone is substituted for 4-chloro-l5 phenyl-1-butanone; 4-[4-(2-naphtha1eny1oxy)-1-piperidy1]1-(4-f1uorophenyl)-1-butanone hydrochloride is produced. M.P. 219-221.5°CEXAMPLE 15 4- (4-(1-Naphtha1enyloxy)-1-piper idyl)-l-(4-fluorophenyl)1-butanone Hydrochloride When in the procedure of Example 13, 4-chloro-l-(4f1uoropheny1)-1-butanone is substituted for 4-chloro-lphenyl-1-butanone and 4-(1-naphthalenyloxy)piperidine hydrochloride is substituted for 4-(2-naphthalenyloxy)piperidine hydrochloride, 4-(4-(l-naphthalenyloxy)-l15 pioeridy1]-1-(4-fluorophenyl)-1-butanone hydrochloride is produced. M.P. 220-222.5°C.

EXAMPLE l6 - (4-(5-Methoxy-1-naphthalenyloxy)-1-pi peridyΠ-1-(4chlorophenyl)-1-propanone Hydrochloride When in the procedure of Example 13, 4-(5-methoxy-l20 naphtha!enyloxy)piperidine hydrochloride is substituted for 4-(2-naphthalenyloxy)piperidine hydrochloride and 3chloro-l-(4-chlorophenyl)-1-propanone substituted for 4ch loro-l-phenyl -1-butanone, 3-[it--(5-methoxy-l-naphtha1enyl oxy)-1-piperidylJ-l-(4-chlorophenyl)-1-propanone hydro25 chloride is produced .

EXAMPLE 17 -(4-(2-Naphthalenyloxy)-1-p i per idyl 1-1-( 4-methylphenyl) 1-pentanone Hydrochloride When in the procedure of Example 13, 5-chloro-l-(4methylphenyl)-1-pentanone is substituted for 4-chloro3C 1-pheny1-1-butanone, 5[^-(S-naphthalenyloxy-l-piperidy1j1-(4-methylpheny1)-1-pentanone hydrochloride is produced. 49888 EXAMPLE 18 4-[4-(l-Methyl-2-naphtha1eny1oxy)-l-piperidy11-1-(4fluoropheny1 )-l-butanone A solution of 5-^7 9 (12.5 mmole) of 4-(l-methyl2-naphthalenyloxy)piperidine, 2.65 g (15-1 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 in vacuo to yield 4-(4-(1-methy1-2-naphthalenyloxy)-1-piperidyl]-l(4-fluorophenyl)-l-butanone.

EXAMPLE 19 6-(4-(4-Tri fluoromethyl-2-naphthalenyloxy -1-pi per idyll 1-(4-methoxyphenyl)-1-hexanone When in the procedure of Example 18, 4-(4-trif1uoromathy]-2-naphthaienyioxy)piparidine is substituted for 4-(l-mathyl-2-naphthalenyloxy)piperidine and 6-bromol-(4-methoxyphenyl)-l-hexanone substituted for 4-chioro1- (4-fluorophenyi)-1-butanone, 6-(4-(4-tri fi uoromethyl2- naphthalenyloxy)-1-piperidyl]-1-(4-methoxyphenyl) 1-hexanone is obtained.

EXAMPLE 20 a-(4-F1uorophenyl)-4-(1-methyl-2-naphtha 1enyloxy)-1piperidinebutanol When in the procedure of Example l8. 4-chloro-l(4-fluorophenyl)butanol substituted for 4-chloro-l-(4fluoropheny1j-1-butanone, a-(4-f1uoropheny1)-4-(1-methy1 2-naphthalenyloxy)-1-piperidinebutanol is produced.

EXAMPLE 21 α-Phenyl -4-(5-f1uoro-1-naphthaienyloxy)-1-piperidinepropanol When in the procedure of Example 18, 4-(5-fiUOro-lnaphthalenyloxy'piperidine is substituted for (1-methyl 2-naphthaleny loxy Jpiper: d i r.e and 5-bromo- 1-phenyl propanol substituted for 4-chloro-l-(4-fluorophenyl)-1butanone, a-pheny1-4-(5-f1uoro-1-naphthalanyloxy)-1pipar id inepropanol is obtained. 49θθ8 EXAMPLE 22 -(4-(5-Methoxy-l-naphtha 1enyloxy)-l-piperidyll-l-'(4f1uoropheny1i^l-propanone A mixture of 25-5 9 (0.1 mole) of 4-(5-methoxy-lnaphthalenyloxy)ρiperidine, 9 g (0.3 mole) of paraform5 aldehyde and 13.8 g (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-msthyl-1naphthaleny1oxy)p i peridy1-1-(4-f1uoropheny1)-l-propanone.

EXAMPLE 25 a-(4-F1uoropheny1)-4-(2-naphthalenyloxy)-1-p iper id i nebutanol To 8.0 g (0.02 mole) of 4-[4-(2-naphtha1enyloxy)15 1-piperidyl1-1-(4-f1uoropheny1)-1-butanone HCI 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 2C bath after which 50 ml of 10f> 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, washed with water and with brine, dried over MgSO4, filtered and concentrated to a solid. The solid material is recrystallized from ethanol/water to give a-(4-fluoropheny11-4-(2-naphtha 1enyloxy) -1-p iper i dinebutanol .

EXAMPLE £4 cl-4-Me thoxyphenyl )-4-( 4-tri f 1 uoromethy 1-2-naphthel enyl oxy;-l-pi peri dinehexanol When in the procedure of Example 23, 6-[4-(4-trifluoromethy1-2-naphthalenyloxy)-1-p iperi dyl]-1-(4-methoxyoheny1)-1-hexanone hydrochloride is substituted for 4-[4(2-naphthalenyloxy)-l-piperidyl)-l-(4-fluorophenyl)-l25 - 49 99 8 butanone, &-(4-methoxyphenyl)-4-(4-trifluoromethy1-1naphthalenyloxy)-l-piperidinehexanol is obtained.

EXAMPLE 25 Tablet Formulation An illustration of a representative tablet formulation of an active compound of this invention is as follows: Per Tablet (a) 4-[(2-naphthalenyloxy)-l- 25.0 mg piperidyl]-1-(4-fluorophenyl )1-butanone hydrochloride (b) Wheat starch 3·5 mg (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 mt; each , EXAMPLE 26 Gelatin Capsule Formulation An illustrative composition for hard gelatin capsules is as follows: Mg (a) 4-[4-(2-naphtha1eny1oxy)-1- 10 piperidyli-l-(4-fIuorophenyl)-1butanone 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 caosules at a net rill of 115 mg per capsules.

EXAMPLE 27 Injectable Suspension Formulation An illustrative composition for an injectable suspension is the following 1 ml anpoule for an intramuscular i njection.

Weight Percent (a) 4- [ 4- ',2-naphtha, eny ioxy )-3pi per i dy1]-1-(4-f,uoropheny1) 1-butanone (particle size <10μ) 1 .0 (b) Polyvinylpyrrolidone (M.W. 25000) 0.5 (c) Leci thi n 0.25 d) Water for injection to make 100.0 The materials (a)-(d) are mixed, homogenized, and filled into 1 ml anpoules which are sealed and autoclaved 20 minutes at 121°C. Each ampoule cont a ins 10 mg per ml \o of novel compound (a).

Claims (5)

1. A compound of the formula (CH,)

2. A compound as claimed in claim 1 wherein z —co—. 10 2'n wherein n is an Integer of from 2 to 5; R is hydrogen, 5 halogen, 0^_ 4 alkyl, Cj_ 4 alkoxy or trifluoromethyl; R^ is hydrogen, halogen, C 1-4 alkyl or C 1-4 alkoxy; and Z is —CO— or —CHOH—; or a pharmaceutically acceptable acid addition salt thereof.

3. A compound as claimed in claim 1 or claim 2 wherein n is 3.

4. A compound as claimed in any preceding claim wherein R^ is halogen. 5. A compound as claimed in claim 4 wherein is 15 fluorine. 6. A compound as claimed in any preceding claim wherein R is hydrogen or halogen. 7. 4-/4-(2-Naphthoxy)-1-piperidy 3/-1-(4-fluorophenyl)-1butanone or a pharmaceutically acceptable acid addition salt 20 thereof. 8. 4-/4-(1-Naphthoxy)-l-piperidyl7-l-(4-fluorophenyl)-1butanone or a pharmaceutically acceptable acid addition salt thereof. 9. A compound as claimed in claim 1 substantially as described in any of Examples 13 to 24. 10. A pharmaceutical composition comprising a compound as 5 claimed in any preceding claim in association with a physiologically acceptable excipient. 11. A composition according to claim 10 in unit dosage form, which comprises from 0.2 to 200 mg of the compound per unit dosage. 10 12. A composition according to claim 10 substantially as described in any of Examples 25 to 27. 13. A process for the preparation of a compound as claimed in claim 1, which comprises alkylating a compound of the formula wherein R is as defined in claim 1, with a compound of the formula halo-(CH 2 ) n -z wherein halo is Cl, Br or I, and n, R, and Z are as defined in claim 1, in a solvent and in the presence of a base for from 24 to 96 hours at a temperature of from 20 49898 14. A method of obtaining tranquilising effects in a non-human patient in need thereof comprising administering to said patient a tranquilizing amount of a compound claimed in any one of claims 1-9.

5. 15. A method according to claim 14 wherein the compound is administered in a dosage of from 0.Q02 to 100 mg per kg of body weight of the patient per day.