NL8004147A - 4-NAFTYLOXYPIPERIDINE DERIVATIVES. - Google Patents

Description

I.

The invention relates to novel derivatives of k-naphthyloxypiperidin. and methods for their preparation. More specifically, the invention relates to novel phenaphthylypiperidines which can be used as chemical intermediates and the N- (benz-benzoylakyl) and N- (hydroxy-β-phenylalkyl) derivatives thereof which can be used. were used as neuroietic tranquilizers, the use of which did cause significant extrapyramidal side effects.

1-phenvl-u - (oerid-1 -vl 'alltancner. Et al., "An important class of calming agent of the central nervous system. Several compounds of this class are disclosed, for example, in U.S. Pat. Nos. 3-? 3 .pt", 3.31 .2 ^ .3, 5T-.S10, 3 · 6> 33, .tPd.tcT and 3.3Ct, 3-2. Although compounds of this type often have a potent anti-psychotic effect, their use has been characterized by the occurrence of severe extrapyramidal side effects and transient hypotension.

It has now been found that the novel V-VU-naphthyloxypiperid-1-yl) -1-phenylalkanones and the corresponding naphthyloxy-phenyl-1-piperidinalcanes of the invention exhibit potent anti-psychotic activity without being significant extrapyranidia induce side effects and little influence on blood pressure.

Novel compounds of formula 1, wherein n is an integer of 2-5, R is hydrogen, halogen, an alkyl, alkoxy or tnflourmethyl group, hydrogen, halogen, an alkyl or alkoxy green and Z is a carbonyl or hydroxyethylene-o Λ Λ A i A 7 - 2 - ♦ * group is useful as an anti-psychotic agent. These anti-psychotic compounds can be prepared from intermediates of formula 2, wherein? -2 is hydrogen, a short chain alkyl or phenyl (short chain alkyl) group and R has the above meaning. Compounds of formula 2 are also new compounds and are part of the invention. The invention also relates to the pharmaceutically acceptable acid addition salts of compounds of formula 1 and formula 2 and individual optical isomers of the compounds of formula 1.

The compounds of formula 1 include «> -_ / 1- (1- and 2-naphthioxypiperid-1-yl) -7-1- (k-substituted) phenyl-1-alkanones of formula 3, and (1- and 2-naphthyloxy-substituted phenyl-1-piperidin canoes of formula k, wherein η, P. and R have the above meanings, the individual optical isomers thereof and the pharmaceutically acceptable acid addition salt and thereof.

The term "alkyl" is used herein to refer to straight and branched chain alkyl groups of 1-k carbon atoms. Examples of alkyl groups are methyl, ethyl, propyl and t-butyl. "Short chain alkyl" in this specification means a straight chain alkyl group having 1-3 carbon atoms. The term "alkoxy" in this specification refers to straight or branched chain alkoxy groups of 1-carbon atoms. Examples of alkoxy greetings are methoxy, ethoxy and isopronoxy. Halogen in this description means fluorine, chlorine or bromine.

The substituent P can be at any position in the naphthalene ring system except for the position occupied by the piperid-k-yloxy substituent.

Preferred embodiments of the invention are compounds of the formula wherein Z is a carbonyl green; Also preferred are embodiments of the invention, wherein n is 3.

Further preferred embodiments of the invention are compounds of formula 1, wherein P is hydrogen or halogen. Preferred embodiments of the invention are also 8004147 1 * compounds ret formula 1, wherein P 1 is a halogen and especially fluorine.

Examples of compounds ret formula 1 are: 5 (1-naphthyloxy) t> inerid-1-yl-7-1 - (k-fluorophenyl) butane-1-one, U- (2-naphthyloxy) piperid-1-yl-7 -1 - (k-fluorophenyl) -butane-1-one, (6-chloro-2-naphthyloxy) piperid-1-yl_7 -1 - (- fluorophenyl) butan-1-one, 3- / U- (5- rethoxy-1-naphthyloxy'ninerid-1-yl 7-i- {h-chlorophenyl) 10 pronan-1-en, k- / u-f 2-naphthylox * foinerid-1-vi / - (reohvlfenvl '-butane— 1 -or 5-methyl-2-naphthyxyxy} oioid-1-vyl-1 - (-sthxyxy-enyl) pentan-1-one, - - ~ 4- (3-ethoxy-2 -naf thyloxy) piperia-1 -yi7 -1-phenyl-but-1-one, 15 5-fluoro-1 -naf thyloxy / piperid-1 -yi7 - 1 - (--fluerphenyl} hexane-1-one (2-trifluoromethyl-1-naphthyloxy) piperid- * -y 1 / -1 - (1-broferyl) butan-1-one, k- (1-naphthyloxy) - «- (1-fluorophenyi } -1-piperidine butanol, 20 (2-naphthyloxy) hj- (1-fluorophenyl} -> -piperidir.ebut ar.ol, 1— (ii_t ri f luo rr.et hvl -2 -naf t hvlc xy '- cc - f snvl— 1 —oTsridinebutancl, hf ^ —327007 ”·“ ^ —Π 3. ^^ / ^ 771.02 ^ -7- '—Ci— f * - * —Cï'CCr'f'SilV * !.) - 1 ^ IHSO Up to 9,110 ^ U- (T-isopropyl-1-naphthyloxy) -luorophenyl) -1-riperidine pentano, (3-ethoxy-2-naphthyloxy} - & - (Ur.ethoxyphenyl) -1-pineridinecutanol, 25 ^ - (2- naphthyloxy - «- (^ - ethylphenyl) -1-piperidinhexanol, k- (8-fluoro-1-naphthyloxy) -®- (b-fluorophenyl) -1-pineridine butanol, and U- (2-methyl-1-naphthyloxy} - # - (phenyl) -1-piperidine butanol.

The invention also relates to the pharmaceutically acceptable acid addition salts of compounds of the formula I which also act as anti-psychotics. Suitable salts are the salts of inorganic acids, such as hydrochloric, hydrobromic, sulfuric and phosphoric, carboxylic, such as acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, fumaric, apuic, tartaric, citric, ascorbic acid , maleic acid, hydroxymaleic acid, 8004147 - k - dihyxroxymaleic acid, benzoic acid, phenylacetic acid, k-aminobenzoic acid, k-hydroxybenzoic acid, anthranilic acid, cinnamic acid, salixic acid, aminosalicylic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, and and sulfonic acids, such as methanesulfonic acid, 2-hydroxy-5 ethanesulfonic acid and p-toluenesulfonic acid.

New intermediates for the preparation of compounds of the formula I are compounds of the formula 2, wherein R is as defined above and R 2 is hydrogen, a short-chain alkyl or phenyl (short-chain alkyl) group, and acid addition salts thereof. Preferred embodiments of compounds of formula 2 are compounds wherein R 1 is hydrogen, a methyl or phenylmethyl group and the compounds wherein R is hydrogen or halogen.

Examples of compounds of formula II are: k- (1-naphthyloxy-piperidine, k- (2-naphthyloxy) piperidine, k- (6-chloro-2-naphthyloxy-piperidine, U- (5-methoxy-1-naphthyloxy-piperidine) , 20 k- (1-methyl-2-naphthyloxy-piperidine, k- (5-methoxy-2-naphthyloxy-piperidine), k- (5-fluoro-1-naphthyloxy-piperidine, 4- (2-trifluoromethyl-1-naphthyloxy-piperidine, h- (6-Bromo-2-naphthyloxy-piperidine, 25 k- (7-isopropyl-1-naphthyloxy-piperidine, H- (H-trifluoromethyl-2-naphthyloxy-piperidine, k- (3-ethoxy-2-naphthyloxy-piperidine, k- (8-fluoro)) -1-naphthyloxy Jpiperidine, U- (2-methyl-1-naphthyloxy Jpiperidine, 30 1-methyl-1 * - (1-naphthyloxy Jpiperidine, 1-methyl - ^ - (6-chloro-2-naphthyloxyJpiperidin, 1- methyl - ^ - (1-methyl-2-naphthyloxy-piperidine, 1-methyl-H- (li-trifluoromethyl-2-naphthyloxy-piperidine, 1-ethyl-k- (5-fluoro-1-naphthyloxy-piperidine, 35-1-methyl-) it-i 7-isoprcpyl-1-naphthyloxy Jpiperidine, 8004147 - 5 - ♦ * 1-propyl-k- (8-methoxy-2-naphthyloxy) piperidine, 1 - (phenylmethyl) -k- (2-naphthyloxy) piperidine , 1- ( 2-phenylethyl) -U- (5-methoxy-1-naphthyloxy) piperidine, 1- (phenylmethyl) -k- (2-trifluoromethyl-1-naphthyloxy) piperidine, 5 1- (phenylnethyl) -U- (6- bromo-2-naphthyloxy) piperidine, 1- (phenylnethyl) -h- (3-ethoxy-2-naphthyloxy) piperidine, 1- (3-phenylpropyl) - ^ - (S-fluoro-1-naphthyloxy) piperidine, and the acid addition salts thereof.

The new compounds retferrule 1 are TO anti-psychotic agents, which can be used in administration alone or in the form of pharmaceutical preparations, which contain the new compounds, optionally in combination with a pharmaceutical carrier, as neuroieptic tranquilizers in warm-blooded animals. Neuroieptic tranquilizers are useful for the treatment of patients who exhibit psychosis symptoms such as schizophrenia or hevise ansst, agitation or aggressiveness. Such agents have a calming effect on psychomotor activity, causing a state of general rest in the patient without inducing sleep.

Patients suitable for treatment with anti-psychotic preparations containing compounds of formula 1 are warm-blooded animals, such as foxes, eg turkeys and chins, and mammals, eg mice, rats, dogs, cats, horses, pigs, cattle, sheep and people.

Pharmaceutical preparations containing compounds of formula 1 may be in solid or liquid form, such as tablets, capsules, powders, solutions, suspensions, or emulsions and may be orally parenterally, eg intraneritoneally, intramuscularly or subcutaneously, or locally, eg. transdermow or transmucosal. The amount containing an effective amount of the new compound as provided in a unitary desing and the nature and amount of the pharmaceutical carrier vary within wide limits depending on the nature of the pharmaceutical prenarate and the body weight of the to be treated. members from the patient population.

Aon i147 - 6 -

Treatment of a patient to be calmed should provide 0.002-100 mg / kg of patient body weight per day to achieve the desired sedative effect. For a human patient, this degree of sedation is achieved by means of an anti-psuchotic preparation in the form of tablets, containing 0.2-200 mg of the active compound and a suitable pharmaceutical carrier, which are taken 1-U times a day. taken.

Small unit doses are required to achieve comparable neuroleptic activity in smaller animal species.

1C The compounds of formula 1, together suitable pharmaceutical carriers, may be in the form of a solid unit dose, such as tablets, capsules and nudes, in the form of a suppository or embedded in a polymer matrix. In the preparation of solid unit dosage forms, it may be desirable to micronise the compound to be used. In solid unit dosage forms, the compounds can be combined with conventional carriers, e.g., binders, such as acacia, corn starch or gelatin; splitting agents, such as corn starch, guar gum or alginic acid; lubricants, such as stearic acid or magnesium stearate; and inert fillers, such as lactose, sucrose or corn starch.

The compounds of formula 1 can also be administered as liquid suspensions or solutions using a sterile liquid, such as an oil, water, alcohol or mixtures thereof, with or without addition of a pharmaceutically suitable surfactant, suspending agent or emulsifier, for oral, topical or paraer administration.

For liquid preparations, the compounds of formula 1 can be suitably formulated with oil, e.g., 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 isopropyimyristate and fatty acid glycerides; with alcohols such as ethanol, isonropanol and oropylene glycol; with water, or with mixtures thereof.

Earth not oil and sesame oil are particularly useful in the preparation of formulations for intramuscular injection. Oils can also be used in the preparation of soft gelatin type formulations and suppositories. T.ater, saline, aqueous dextrose and related sugar solutions and glycerols, such as polyethylene glycol, can be used in the preparation of liquid formulations, which may suitably contain a suspending agent such as pectin, carborate, methyl cellulose, hydroxypropyl cellulose or carhoxymethyl cellulose. , as well as buffers and preservatives.

As an example, upon administration, var.

10 (2-Naphthyloxy) piperidyl-7- (fluorophenyl) but-1-c-bydrochloride intraperitoneally in mice at a dosage of var. 2, Cc mg / kg, the total toxicity of d-amphetarin occur in 59c of the mice, which were tested according to the method described by J. Surn et al., Arch. Int. Pharmaccdyn. 11, 2 ° C-15 295 (1955), demonstrating the antipsychotic activity, while requiring a dose amount of C, 9d mg / kg of the known sedative chloropractin to achieve such a response. Similarly, compounds of the invention show neuroleptic activity by preventing harmful preening in mice, which are tested according to the method described by Λ. kandel et al.,

Fed. Proc., J £ (1, part 1 ;, 2¾ (i $ 6c).

The neuroleptic strength of the compounds is associated with a reduced tendency to cause extrapyramidal side effects in patients treated with a neuroleptically effective dose compared to known anti-psychotic agents. Indicative for the diminished extrapyramidal activity of the compounds according to the invention, upon introperitoneal administration of 2-naphthlyxy) nyperid-1-yl7-1 - (^ - fluorophenyl) hutan-1-onhydrochioride to mice, a dose of 3 ^, 0 mg / kg needed to counteract the behavioral action of apomor-fine in 50¾ of the mice, which were tested according to the general method described by PAJJanssen et al., In Arzneimittel-Forschung, J0, 1003 (I960), while only 35 1, ¾ mg / kg chlorpromazine was required for such an effect to be a Λ Λ L 4 /. 7 -. - 8 - obtain.

Compounds of formula 1 are prepared by alkylating intermediate compounds of formula 2a, which are compounds of formula 2, wherein Pg is hydrogen and R has the meaning above. Compounds of formula 2a are themselves prepared by dealkylation or debenzylation of compounds of formula 2b, wherein P 1 is a short chain alkyl or phenyl (short chain alkyl) group and R has the above meaning representing compounds of formula 2, wherein is a short chain alkyl or phenyl (short chain alkyl) group. This shows that all compounds of formula 2 are useful intermediates for the pharmaceutically useful compounds of formula 1. Compounds of formula 2 are also known. are part of the invention.

Compounds of formula 2b are prepared by reacting a 'T-substituted-1-piperidinol salt of formula 5, wherein R? a short chain alkyl or phenyl (short chain alkyl) group + ^ · · ...

and M is an alkali metal catalyst, such as potassium, sodium cf lithium, with a naphthyl fluoride of formula f, wherein P is as defined above, primarily a 1- (short chain alkyl) or 1-phenyl (short chain alkyl) -i- naphthylcxyniperidine of formula 2b. The compounds of formula 2a, wherein p is hydrogen, are prepared by dealkylating H-substituted compounds of formula 2b using a chloroformic ester of formula 25, wherein 2,2,2-trichloroethyl; vinyl, substituted vinyl, benzyl, substituted benzyl or cycloalkyl is reacted with the compound of formula 2b in the presence of a proton-incorporating compound to give a '- (P 1 -oxycarbonyl) - * 1- (naphthyloxy) piperidine of formula 7, wherein R. and a ,.

30 have the above meanings and the β-carbonycarbonyl green is removed using a weak reducing agent, such as zinc dust in acetic acid or methanol, or by acid hydrolysis, as shown in Scheme A.

Otaphthalene fluorides of formula 6 are known and can be prepared by methods known in the art, such as described by T.Adcock et al., Ir. 8004147.

J. Am. Chem. Soc. 89 (2), 386-390 (1967) and in J. An. Chem. Soc. 98 (7), 1701-1711 (1976).

Piperidinol compounds of formula 5 are prepared by reacting the corresponding 1-short chain alkyl or 1-phenyl (short chain alkyl) piperidinol with a strong base such as an alkali metal hydride, an alkali metal amide or alkyl lithium by well known methods. The pioeridin salt is reacted with the naphthyiflucride of formula 6 in the presence of a polar aprotic solvent, at a temperature of 50-200 ° C or at the boiling temperature of the solvent for 1-2 hours. Suitable solvents are tetrahydrofuran, dimethoxyethane, disrlyne, dicxan, hexamethylphosphoric triamide, dimethylacetanide, dimethyl sulfoxide, 1-methyl-2-pyrrolidone, sulfol-15-lan and especially dimethylformamide.

The reaction is passed through diluent, just brought to rest and the resulting H-substituted compound of formula IIb or an acid addition salt thereof is isolated in a conventional manner, eg the reaction mixture can be progressed, filtered and the solvent removed, thereby yielding the product. isolated, which is then purified by recrystallization. very sad. C-suitable solvents for the recrystallizer. are, e.g., chain-chain aliphatic alcohols, such as methanol, ethanol and isopropanol; ketones, such as acetone and butanone; esters, such as ethyl acetate; Hydrocarbons, such as hexane and combinations thereof.

The 1-short chain alkyl or 1-phenyl (short chain alkyl) -1i-naphthyloxypiperidine of formula 2b thus prepared is then reacted with an ester of chloroformic acid in the presence of an aprotic solvent and preferably honor.

Acid scavenger to form a carbamate of formula 7 which is then cleaved to yield the corresponding 1-unsubstituted U-naphthyloxypiueridine of formula 2a. Suitable chloroformic esters are compounds of formula 9 which are P 1 -oxycarbonyl substituent. which can be split off from the nitrogen atom of the compound with 800 A 147 -. - 10 - Formula 7 hydrolytically or under reducing conditions, whereby the naphthalene ring is not hydrogenated.

Such chloroformic esters include the 2,2,2-tricloroethyl ester which can be cleaved by reduction with zinc dust or by electrolysis; the benzyl ester, benzyl esters, which are substituted by phenyl, methoxy, methyl, phenylazo, cyano, bromine or chlorine, vinyl esters and cycloalkyl esters, such as the cyclohexyl, cyclopentyl, adanantyl and isobornyl esters, which can be separated by acid hydrolysis using a strong acid, such as hydrochloric acid or hydrochloric acid, or the weak acid agent, such as trifluoroacetic acid, in a suitable colossizing agent. (Thimoric acid esters suitable for displacing alkyl and benzyl substituents from tertiary amines and methods suitable for splitting off the various β-oxycarbonyl greetings from the nitrogen atom are described by M. Bodanszky et al., in Peptide Synthesis, 2nd Ed. (John Viiey and Sons), pp. 21-37 (^ 976) and in U.S. Patent 3,925,9-1 The preferred chloroformic acid ester for deaikylation of compounds having Formula 2, wherein an i'-short chain alkyl or phenyl (short chain alkyl) is green, is 2,2-trichloroethyl chloroformate.

Suitable solvents for the reaction of an N-substituted compound of formula 2b with a chlororic acid ester are anrotic organic solvents, e.g.

Ethers such as diethyl ether and tetrahydrofuran, aromatic hydrocarbons such as toluene and benzene, chlorinated hydrocarbons such as chloroform, dichloroethane and methyl chloride, or mixtures thereof. The preferred solvent is methylene chloride. The reaction can be carried out in the presence of a small amount, eg 1 to 5, based on the amount of the compound of formula II b, of a proton-binding agent, which may consist of an inorganic base, such as sodium or potassium carbonate, a strong organic base, such as triethyl amine, or a mixture thereof. The reaction mixture is heated to a reflux temperature of 8004147 at a temperature in the range of 0 ° C. -11- of the solvent held for 1-96 hours. The 1- (P-oxoxycarbonyl) -U-naphthyloxypiperidine of formula 7 thus obtained is isolated, e.g. by extraction in an organic solvent and evaporation of the solvent according to well known methods and the P 1 -oxycarbonyl group is split off with an appropriate method.

In the preferred embodiment of the invention, a 1-short chain alkyl or 1-phenyl (korf chain alkyl) substituted compound of formula 2b is refluxed in methylene chloride with a slight excess, eg 1.01-1.3 equivalents, at preferably 1.1 equivalents, of 2,2,2-trichloroethyl chloroformate in the presence of an amount of a proton-binding agent for 6-2 hours at a temperature in the range of 15 ° -0 ° C, preferably at room temperature.

The cane product is extracted into ether, washed with dilute acid and concentrated in vacuo. The 1- (2,2,2-trichloro-ethoxycarbonyl) -naphthoxypiperidine thus formed is dissolved in a solvent consisting of acetic acid, aqueous acetic acid, a short chain alkanol such as methanol, an aqueous short chain alkanoi and preferably a mixture of acetic acid, water and an ether, such as%, * -v tetrahydrofuran. 3i, j a temperature of 0-50 ° C, preferably room temperature, 1-5 equivalents, preferably 2 equivalents, zinc dust are added gradually with stirring and the reaction is allowed to proceed for 1-6 hours until gas evolution is completed. likes. The solvents are evaporated and the H-unsubstituted compound of formula 2a is separated from the residual zinc salts by basic adjustment, extraction in an organic solvent, washing to remove water-soluble impurities, conversion to a water-soluble acid addition salt, washing with organ-30 organic solvents to remove neutral organic impurities and reset to basic. The J-unsubstituted compound is recrystallized by conventional methods, preferably in the form of an acid addition salt thereof, from suitable solvents, such as aliphatic alcohols, chains.

35 esters and combinations thereof.

800 41 47 • * - 12 -

Free bases of formula 2, prepared according to the method described above, can be converted into the acid addition salts by reaction with a suitable acid according to well known methods.

The compounds of the formula 1 are prepared by reacting a piperidine derivative of the formula 2a, in which is hydrogen, with a small excess of a "-j-halo-alkylphenylketone or a" -halo-1-phenyl-1-alkanol of the formula ? in the presence of an excess of an acid concentrator, such as, for example, sodium bicarbonate, potassium bicarbonate, sodium carbonate or sodium carbonate, and optionally a small amount of potassium oxide in a suitable solvent. If desired, two or more equivalents of the piperidine derivative of the formula 2 relative to the compound of the formula 5 can be used in place of the mineral base acid acceptor. Compounds of formula 1 are prepared from the acid addition salt of the compound of formula 2a by reacting the acid addition salt with a compound of formula 3 in the presence of at least 2 equivalents of the mineral base acid acceptor. The reaction mixture can be reacted within a wide temperature range. Generally, a reaction temperature of 20-1800-10 is used. The reaction is carried out for 1-U days, during which time any water formed can be collected. As examples of suitable solvents for this reaction are mentioned toluene, xylene, chlorobenzene, methyl isobutyl ketone and short chain aliphatic alcohols such as ethanol, propanol and butanol.

After completion of the reaction, the product is isolated by conventional means, eg, the reaction mixture can be filtered and the solvent removed to isolate the product. Alternatively, the filtrate can be treated with an ethereal solution of a suitable mineral or organic acid to yield the corresponding salt of the product. The crude product is filtered off, purified by recrystallization and dried. Examples of suitable solvents for recrystallization are short chain 8004147 -. - 13 - 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 1 can be represented by scheme 3, wherein n, R, and Z have the above meanings and halogen denotes a reactive halogen such as bromine, chlorine or iodine.

Compounds of formula 8 are commercially available or can be prepared by the methods known per se. For example, compounds of formula 8, wherein Z is a group 0 = 0, may be prepared by reacting the appropriate of-halofreeralkanoyl halide and a (substituted) benzene in the presence of a levis acid, such as aluminum chloride, or by (b-substituted) phenyl Grignard reagent to react with 15 an appropriate halhaloalkyl nitrile. Compounds of formula 8, wherein Z is a group CFOH, can be prepared by reduction by chemical reduction components or catalytic hydrogenation of the corresponding i- (U-substituted} phenylH> J-haloalkanes of formula 8, prepared as described above Reaction or reaction of honor: 1-substituted} ferylGrirnard reagent with a suitable hal-halmene alkane.

3 - - - naphthyloxypiperi d-1-yl yl-ferylorcnone, compounds of formula 3, wherein n equals 2, are also prepared by reacting a compound of formula 2, wherein 25 is hydrogen with a suitable acetofer.cn and formaldehyde.

k-naphthyloxy-1-piperidinic can with formula k can be prepared by reducing alkanes with formula 3. Suitable methods for reducing ketone. Alcohols are known in the art and include catalytic hydrogeneration and reduction with chemical odorants.

For example, for catalytic reduction, a ketone rhee formula 3 can be dissolved in honor. solvent such as a side acid, ethyl acetate or a short chain aliphatic alcohol such as 8004147 -. - Lit - methanol or isopropanol and the solution is stirred in the presence of hydrogen at a pressure of 1-1 * at. and room temperature, i.e. 20-25 ° C, in the presence of a suitable catalyst, such as platinum, platinum oxide or rhodium, until an equivalent of hydrogen is consumed.

Alternatively, the ketone of formula 3 can be reduced by reaction with a suitable chemical reducing agent. The ketone can be refluxed, for example. are heated in ether for 1 to 5 hours with metal hydride, eg lithium alumina hydride or diborane, or reacted for half an hour to 3 hours at a temperature of 0 ° C to the reflux temperature of a short chain aliphatic alcohol such as a solvent, such as methanol or ethanol, with a metal borohydride, such as sodium borohydride or potassium borohydride, whereby an alcohol of formula 1 * is obtained. Other reagents suitable for the reduction of a ketone to an alcohol beam are obvious to those skilled in the art.

9

Compounds of formula 1, which are prepared in the form of free bases, can be converted into their acid addition salts by reaction with a pharmaceutically acceptable acid.

The optical isomers of ontically active compounds of formula 1 can be separated using any suitable resolving agent. Optical optical var.

For example, compounds of formula 1, wherein Z is a hydroxymethylene group, may be separated using a (+) - or (-) - dinaphthylphosphoric acid derivative or a salt of that derivative and an optically active base according to the method described by R. Viterbo et al., In Tetrahedron Letters, 1971 (1 * 8), p. 1 * 617-30 1 * 620.

The examples below serve to illustrate the invention.

Example I

lt- (2-Naphthyloxy) -1- (phenylmethyl) nireridine hydrochloride 35. On a stirred suspension of 1.80 g (37.5 8004147 * 1 - 15 mmole) washed with pentane 5 C 4 sodium hydride dispersion and 50 ml dry dinethylformamide, a solution of k, 75 g (25.0 mmol) of 1-enylmethyl-U-piperidinol in 20 ml of dry dimethylformamide is added under argon followed by a solution of 3.83 g of 5 (26.2 niol, 1.05 eq.) 2-Fluoraphthalalene in 20 ml of dimethylformamide.

The mixture is heated to 75 ° C for 23 hours, cooled, poured into ice water and extracted twice with ether. The extracts are washed with water and saturated brine, dried over magnesium sulfate and filtered. The filtrate is treated with HCl / methanol and the obtained 1- (2-naphthyloxy) -i {phenyl-methyl) piperidine hydrochloride is orcrystallized from butanone / methanol. fmpt. 2 ^ 2-2 ^ 1 ° C Example II

U- (1-naphth? / 'Loxy) -1-phenylmethylrinerine hydrochloric acid. When in the method of Example 1' -fluoro-naphthalene is used instead of 2-fluoro-naphthalene, U- (1-naphthyloxy) -1- ( phenylrethyl) piperidine hydrochloride formed.

Mp. 222-22h ° c.

Example III

20 k— (5-methcxv-1 —η & ίΐ'ηνίοχν) - * - * i'envLre't bv2_ * '? · ** · * a TJanr * eer ι, η. When using 5-methoxy-1-fluoro-naphthalene, in the form of 2-fluoro-naphthalene, k- (5-methoxy-1-naphthyloxy) -'- {phenylrethyl) -irerine hydrochloride is formed .

Example IV

h - (^ -m.ethyl-2-naphthyloxy) -1-methylrirerid inehydric chloride

In the method of Example 1, when 1-methyl-2-fluoroaphthalene is used instead of 2-floro-naphthalene and 1-methyl-pireridincl is used instead of 30 1-phenylmethyl-k-pxneridinol, k- (1-Methyl-2-sodium methylcyl; -imethylniperidine hydrochloride formed.

Example V

l ;-( li-trifluoromethvl-2-r.afthylox: /) - 1 -msthylnireridinolhr / drochloride

In the method of Example 1, when U-tri-35 fluoromethyl-2-fluoroaphthalene is used in place of 2-fluoro-AO i 1 L 7. 16-Naphthalene and 1-ethyl-piperidinol are used instead of 1-phenylmethyl-k-niperidinol, 1- (h-trifluoromethyl-2-naphthyl-oxy-1-methylpiperidine hydrochloride) is formed.

Example VI

5k- (5-fluoro-1-naphthyloxy) -1-ethylnineridine hydrochloride

When in the method of Example 1 1,5-di-ethyl-naphthalene is used instead of 2-floraphthalene and 1-ethyl-piperidinol is used instead of 1-phenylmethyl-kp ip eri di no 1, k - (5-fluoro -1 - n af t hy lo xy) -1 -et hy lp iperi di ne -10 hydrochloride formed.

Example VII

k- (2-naphthyloxyjoineridine hydrochloride

To a stirred solution of .6 g (Q, 20U mol) k- (2-naphthyloxy) -1-phenylmethylpiperidine in 500 µl methylene-15 chloride are added 37.0 ml (0.26 µmol) 2.2.2- trichlorethyl chloroformate and about 2C0 mg of potassium carbonate added. The mixture is stirred at room temperature for 8 hours and poured into a volume of ether and water. The organic xase is washed with dilute hydrochloric acid and aqueous potassium carbonate, dried over magnesium sulfate and concentrated in a container.

The resulting 1- (2,2,2-trichicorethylo-carbonyl) -k- (2-naphthyloxy) piperidine is dissolved in a mixture of 250 ml acetic acid, 250 ml tetrahydrofuran and 125 ml water. 28.5 g (0.36 mole) of zinc dust is added in portions with stirring and the exothermic reaction is allowed to ionize for 2.5 hours. The mixture is filtered and the co-solvents are removed in a container. The residue is partitioned between ether and aqueous sodium hydroxide, and the organic phase is washed with water and extracted with dilute aqueous hydrochloric acid. The acid extracts are washed with ether, made basic with sodium hydroxide and p-extracted with ether and toluene and the organic solution is washed, dried over magnesium sulfate and concentrated in vacuo to redissolve 2-naphthyloxy) piperidine. in ethanol / ether and treated with dry HCl and the hydrochloride salt is recrystallized from butanone / methanol.

^ 800 Λ 147 - 17 -

Mp. 229.5-231.5 ° C.

Example VIII

U- (1-haphthyloxy) uineridine hydrochloride

In the method of example, 7TI 5 naphthyloxy) -1-enylrethyi} piperidine is reused in place of U- (2-naphthyloxy) -1-phenylirethyl) pireridine, * '1- (lr.aphyllcxy} -piperidinehydrochloride -form) .d.

Example IV

v * · 'ν »τνΆ'ί- ^" -y 1 q> / * + Τ' * Τ '^ v, G'n7,]' y, r'.r, r '' C

1 Q * r>.-V Λ '"" ^ VrOC0 "/ O **" r "**" T ”V __ V. -.

yQ wa * · V »- - ^ - ^ OV» - r "* o-, v ^ r ^ V \ v '-s ^ * -λ Ί-ΓΓ' ^ dT / * -ν 'place' from - *, 2-n? .F'tbfl.v "r) —1-," -3n'rlretb.yl'rireriiir.e becomes - - "-. i r + -. ,, \ · ·, Y -v »ny 'Trtwft-i · * - ƒ - —τ-> G -» - * »» / - »v * · *" ifi; —O **> - ·, Y »tv --τ Y- ~ <£ -v» V ao ^ o, <r 1 ^ li—. '”- ** _" * - >> "f> ^^ - r-- ^ - τ' λυ * "· ^ ^ '' Ύ ^

Wq Τ '* "0 Λ Υ *» Τ * Λ τηα “" ^ Γ * ν Ώ ^ · »3' TC ^ * '·' 120! Ζ. Fluoro-1-narthyloxy} - Ethyloiteridine is reconstituted in the region of 79-79. "ΛΤ" »·· TviCit- v> -r ^ 1 * 'y» 0> *' ΜΔ τ. * Λ · ν * ^ ** · tl - i - rsiItbYlcxv> o i. ^ Θ 2 * 2 ^ 2 .η Λ r * d, Fo Y * '· *' ~

Example XI

^ τ -η »¢ 5 V» / «* Ty · * * r-»? - · - '* V * t * ^ "*> *« <* », τ τ -4 ·· v * τ *, . ·. » , «5 -v» 1 * * * - y _ ^ '(/ _, -Λττ --tt' τ y τ * yyy »fv * y -T» vit "<*> .1« «· ',. r + ir \ · ** «· * ->. τ xy-1 -naphthyloxy) -1 - · 'f enyirethyl; r inert dine in * trb *, 2-di chloro-β" νΠ8,3.η vordis ίτ ΐ ΐ χ "X * s s cin e e e e c c cs cs cs van van van van van van van van van van van van van van van van van van van pl pl en en en en en en en en en en en en en en en en en en en en en en en hl. .reratu'jr werterd and in vakuür core er ”C rö6 ^ d. * po ^ 3.1 so Terkreep 5 ", r '' ^ Tbox" r / '- 1, "r9.f, b ^ vlcy, * ri ,," 1 - (f'gnvloxy'Gnirbcn "* -' '! yrireridine 7 * 70rdT 2 'j.' ^. R yen - ^ r 'm "n2 Ir ^ e ^ rorcl? 0 p-eroerd? V3, srdoor 1 - (^ o jor_ · ^“ Γ. ^ D "t'" vlc'cv '^ r £ r cri c Ir er v ^^ ocr lor i. * “de is ververting ·

Example XII

L_ {1 —τη ^ τ ^ vl — rr * ^ * ^ 'v ^ τΛν »· * ^ TT' ^ e ^ Td '' ηΛ * Λvd ^ οΛ ^" * ^ 43 '' represent the retbode far example ' i X "" ^ * - 35 v β T hy 1—2 - r 8. fthy 1 o xy j - 1 - Try ^ lrireridire until reaction becomes rsbraert \ 8004147 ¥ ·.

- - With benzyl chloroformate, the formed 1- (i-methyl-n-na-trvioxy) -1- (phenyl-ethoxycarbonyl} piperidine yields hydrolysis 1-C1-methyl-2-naphthyioxynioeridine hydrochloride.

Example XIII

5 1- / ~ * U- (2-naphthylox) -1 -oineridyl7-1-fer.yl-1-butanone hydroch. L nn '^

Sen colossi ns: from 5.67 g (25 mol) II - (2-naphthyicxy) ciperidine, 5.0 p (27.1 mol) 1-chloro-1-phenyl-1-cutanone, 0.1 g potassium gcide and 1.5 p potassium hicarhonate in 100 ml of toluene are heated for 1 h with stirring for 1 h. steam bath. Pet 10 mixture is partitioned between ICO m in amounts of alcohol / ether and water and the organic phase is dried coven MgSOj An excess of HCl in ether is added and the precipitate formed is recrystallized from m / m -nol / butanone to give 1- (2-raphthyl-l-1-piperidyl) -1-phenyl-1 -15 but anon hydrochloride ride is obtained.

Example XIV

1-7 "" 1- (2-raphthylor] -1) -roeridyl J -1- (1-f-lucrphenyl) -1-cut anenhvd-n-chloride

Prior to using the method of Example XIII 20 1-chiocr-1- (1-fiucrphenyl) -1-butanone is substituted for 1-chlorcor-1-phenyl-1-cutanone, 1-V 1-2-r afthyioxy) - '-rirerid'-7-1-(α-fluorophenyl) -1-butanone hydrochloride. f-mar 2i ° -221.5 ° C.

Example XT "25 l- / ~ 1- (1-naphthylor.") - 1-citieridyl7-i- (1-fluorophgr. V1) -1-bnt, anhydrous chloride

Before the irethede of Example XIII 1-chloro-1- (1-fluorophenyl) -1-butanone is used in place of 1-chloro-1-phenyl-1-hutanone and 1- (1-naphthyloxy) rioididine hydrochloric acid The ride used forms 1-Λ1- (1-naphthyioxy) -1-niperidyl? -1 - (fluoro-phenyl) -1-butanone hydrochloride in place of U- (2-naphthyloxy) -nineridine hydrocloride. 220-222.5 ° C.

Example X'v.

3- / "1- (5-methoxy-1-naphthyloxy) -1-nineridyl" -1 - (1-phenylphenyl) -1-35 nronanone hydrochloride 78004147 ". »- 1Q -

In the method of example UTT, when li (5-methoxy-1-naphthyloxy) piperidine hydrochloride is used in place of U- (2-r -aphthyloxy) piperidine hydrochloride and 3-chloro-1- (k-chlorophenyl) -1- propanone is used instead of ^ -chloro-5 1-phenyl-1-butanone, 3- / k- (5-methoxy-1-naphthyloxy) -1-riperidyl 7-1 - (^ - chlocrphenyl) -1- propanone hydrochloride.

Example XVII

5 - / - (2-raphthyloxy) -1-nineridyl 7i-r-ethylfer.yl} -1-rer. 1- (1-methylphenyl) -nentancn hydrochloride is used instead of k-chlorcor-1-phenyl - "- cutanor. Becomes 3-^ - ^ 2-naphthiνίο xy) -1-niperidyl7-1 - ( 1-methylethylphenylpentanic hydrochloride formed.

Example XVIII

li- / '- "ethyl-1-naphthylzyy) - ~ -nineridyl» -fluorfery1 --- butanone

Zen ouiossir.g var 3 »** 7 s? 12.3 mm @ -1. -1. -Ethyl-2-naphthylyxyminineridine, 2.6. ~ [3.1 mmol) k-chloro-20- (fluorophenyl) -1-tutarone, 5.2 g (52 mmole of potassium bicarbonate and a pinch of potassium iodide in n. Ml of toluene. heated under evaporation for 3 hours. The mixture is partitioned between toluene and water and the organic phase is washed with saturated saline, dried over iragne sulfur and concentrated over 1 hour to give 1- (1-methyl-2-naphthyloxy). -1-piperidyl-7-1 - (1-fluorophenyl} -1-butanone is obtained.

Example XIX

6-7 "1- (h-trifluoromethyl-2-naphthyloxy) -1-methylmeryl 7-1 - (i-metho xy-phenyl) -1-hexanone

When in the method of Example XVIII

b- (U-trifluoromethyl-2-na? thyloxy) -niperidine is used instead of 1 * - (T-methyl-2-naphthyloxy Jpueridine and 6-bromo-1- (1-m.ethoxyphenyl) -1-hexanone instead of k-chloro-1- (U-fluorophenyl) -1-butanone, 6-1- (1- (trifluoromethyl-2-naphthyl-oxy) -1 -oineridyl7-1- (k-inethoxyphenyl) ) - 1-hexanone is obtained.

i _ * y 8004147 - 20 -

Example XX

ot- (ί-fluorophenyl) -k- (1-methyl-2-r-afthyloxy) -1-niueridine butanol

When U-chloro-1- (k-fluorophenyl) butanol is used in place of h-chloro-1 - fluorophenylM-butanone in the method of Example XVIII, a- (fluoro-phenyl) -M 1-methyl-2 naphthyloxy) -1-piperidine butanol.

Example XXI

<x-phenyl-i- (5-fluoro-1-naphthyloxy) -1-pineridine proOanol

In the method of Example XVIII, when U- (5-fluoro-1-naphthyloxy) niperidine is used instead of (1-methyl-2-naphthyloxy) piperidine and 3-brccm-1-phenyl-n-panpanol is used instead of H- chiocr-1 - ((- fluorophenyl) -1-butanone, a-phenyl-k- (5-fluoro-"-naphthyloxy) -1-? -peridine procanol is obtained.

Example XXII o --- 3- / U- (5-methoxy-naphthyloxy) -1-cineridyl / -1-i-fluorophenyl / - * -nronance

A mixture of 25.5 g (0.1 mole) of h- (5-mathoxv-1-naphthyloxy / piperidine, 9 g (0.3 mole) of parafromaldehyde and 13, B gm (0.1nol) h'-fluoroacetophenone in 100 ml isopropanol, containing 2 drops of concentrated hydrochloric acid, is heated under reflux for 2 hours, the mixture is filtered and the filtrate is concentrated to about 100 ml and cooled, the precipitate obtained is recrystallized from ethanol, whereby 3- [k- (5-2 [mu] -ethyl-1-naphthyloxy) -piperidyl-7-1- (k-fluoro-phenyl) -1-nropanone is obtained.

Example XXIIT

0t - (U-fluorophenyl) -1- (? -Naphthylcxy) -1-nineridine butancl

To 1.0 g (0.02 mol) of k- / UU- (2-naphthyloxy) -1-nineridyl 7-1 - (h-fluorophenyl) -1-hutanone hydrochloride in 50 ml ml 30-methanol was added 1.1 g (0.05 m.cl) of wet ri unmet h anoate and then 2.7 g (0.05 mole) of potassium bohydride and the mixture is stirred at room temperature for 2 hours. The methanol is removed under reduced pressure on an interference bath, after which 50 ml of 10% sodium hydroxide are added. The mixture is left for 15 min.

800 4 1 47-2 · Stirred and 100 ml of chloroform are added. Stirring is continued for half an hour. The chloroform layer is separated and combined with two 25 ml aqueous phase chloroform extracts, washed fatty water and with saturated brine, dried over magnesium sulfate, filtered and concentrated to a solid. The solid material is crystallized from ethanol / water to give o <- (h-flufsilyl) -b-f2-oafnyyxy) -1-piperidine butaucl.

Example XXTV

10 [- (1-methoxyfer.v1) -1- (1-trifluoromethyl-2-naphthyloxy] -1-rineridir.e-hexanol

When in the red method of Example TXT II (b-trifluoromethyl-2-naphthyl-xyl--1-olideyl / -1- '-6- "ethoxy-phenyl) -1-hexanone hydrochloride is used instead of i-15 2-naphthylcyl; -1-oireridyl] - "- C -flucrphenyl -" - butanone is obtained. {X ^ n ^ ^ nvl) —1— (olymethyl * 1 -naphthyl] xyl] - "—rmeridire— hexanol .

Example XXV Tablet formulation. For example of a representative tablet formulation of an active compound, the invention is as follows: Primary tablet (a) U - / "(2-naphthyloxy) -1 -oiperidyl7-1 - i" -flucr - 25 phenyl) -1-butanone hydrochloride 25.0 ng (b) Wheat starch 3.5 mg (c) Lactose 10.0 mg (.d) Magnesium stearate 0.5 mg

A granulation obtained by mixing lactose with the starch and granulated starch paste is dried, sieved and mixed with the active ingredient and magnesium stearate. The mixture is compressed into tablets, each weighing 39.0 mg.

Example XXVI

35 Gelatin formula formula ^ \, 8O04 1 47 - 22 -

J

An example of a composition for hard gelatin capsules is as follows: (a)! - / _-!; - · (2-naphthyloxy) -1 -piperidy17-1 - (k-? Fluorophenyl) -1-t) utanon hydrochloride 10 (b) Talc 5 (c) Lactose 100

The formulation was prepared by passing the dry powders of (a) and (b) through a fine-mesh sieve and mixing them well. Fat powder is then filled into hard gelatin capsules with a net filling density of 115 mg per canister. Example XX7TI

Indicate susceptible suspension

An example of a composition for an injectable suspension is the following 1 ml ampoule for an intramuscular injection.

• Case 7 (a) U - / - (i - (2-naphthyicxy) -1-niperidyl_7-1-fluoro-phenyi) -1-butan (particle size 10 µm) 1.20 (b) Polyvinylpyrrolidone (mcl wt. 25,000 pc (c) Lecithin 0.25 (d) Water feed injection in addition to 100.0

Materials (a) - (d) are mixed, homogenized and filled into 1 ml ampoules, which are sealed for 25 minutes and heated at 121 ° C in an autoclave for 20 minutes. Tender arvnul contains 10 mg per ml of new compound ία).

M? 8004147

Claims (10)

1. Novel 1-naphthyl-cypiperidine derivatives of the formula 1, wherein n is an integer of 2-5, p hydrogen, halogen, a straight or branched chain alkyl with 1-1 carbon atoms, a straight or branched chain alkoxy group with 1-1 carbon atoms or a trifluoromethyl group, P. hydrogen, hal is a straight or branched chain alkyl group of 1 to 1 carbon atoms, a straight or branched chain alkyl group of 1 to 1 carbon atoms and Z is a carbonyl or hydrocarbon methylene green, a separate · * "" · 10 isomer or a pharmaceutically acceptable acid addition salt 2. Naphthromic / proline eriwin whey according to claim 1, characterized in that Z is a carbomethyl ether whey of claim 1, characterized in that where n equals 3 · ip ï * a ^ ν'1 cone * "-rr» 1 p * o — o therein w is a halogen. 5 * ο. * · "" · * · ** "CXVTT3 ^ * 1.γΛ * claim 1, characterized in that it contains fluorine 20 o. Afthwlcx '/' ttrertdtne'leriwaaf wolme ** ^ one or more wan wec ^^^ an ^ e conclu sies, —0— -o—> 0 ——. ^ -> ^ ca— therein ~ hydrogen is cf an entity. 1-Naphthyloxpiperidir derivatate according to claim 1, characterized in that it is 1/1 (2-rafthwloxw) -piperidyl-7-1- (1-fluorophenyi) -1-butanone or a pharmaceutical valuable acid addition salt thereof. 8. 1-Naphthyicxyrineridine derivative according to claim 1, characterized in that it is 1- (1-Naphthyloxy) -piperidyl-7-1- (1-fluorophenyl) -1-butarone or a pharmaceutically acceptable acid addition salt thereof. 9. Method for obtaining a calming effect on a patient in need thereof, characterized in that the patient is given a calming amount of a compound of formula 1, wherein n is an integer of 2-p, H is hydrogen, halogen, a straight or branched chain alkyl - *: ί * - IV1 8004147 - 2k - group of 1-¾ carbon atoms, a straight or branched chain alkoxy group of 1-¾ carbon atoms or a trifluoromethyl group, n1 hydrogen, halogen, a straight or branched chain alkyl group of 1-¾ carbon atoms or a straight or branched chain alkoxy green of 5 1-¾ carbon atoms and Z is a carconyl or hydroxymethylene green, a separate optical isomer or a pharmaceutically acceptable acid addition salt thereof. 10. A method according to claim 0, characterized in that the compound is administered in a dose of 0.002-100 mg / kg body weight of the patient per day. 11. Process according to claim 9 or 10, characterized in that the active compound used is 1/2 (2-naphthyloxy) -1-piperidyl-7-1-fluorophenyl) -1-butanone or a pharmaceutically acceptable acid addition salt thereof. used. 12. Process according to claim 9 or 10, characterized in that the active compound used is k - / - k - (1-naphthyloxy) -1-piperidyl-1-7-fluoro-enyl) -1-butanone. or use a pharmaceutically acceptable acid addition salt thereof. Pharmaceutical oreoarate, characterized in that it contains an amount suitable for administration of a naphthyloxyloeroidine derivative of the formula 1, wherein n is 2-5, F hydrogen, halogen, a straight or branched chain alkyl group containing 1-¾ carbon atoms , is a straight or branched chain alkoxy group having 1-¾ carbon atoms or a trifluoromethyl group,? Hydrogen, halogen, a straight or branched chain alkyl group of 1-¾ carbon atoms or a straight or branched chain alkoxy group of 1-¾ carbon atoms and Z is a carbonyl or hydroxymethylene green, a separate optical isomer or a pharmaceutically acceptable acid addition salt thereof. 30 1¾. Anti-psychotic preparation, characterized in that it contains an anti-psychotically effective amount of an h-naphthyloxyrineridine derivative of the formula 1, wherein n is 2-5, p hydrogen, halogen, a straight or branched chain alkyl group 1-h carbon atoms, a straight- or branched-ak 35 chain alkoxy growth ret 1-¾ carbon atoms or a trifluoromethyl- 8004147-25 group, hydrogen, halo, straight or branched alkyl group ret 1-k carbon or a straight or branched alkoxy group is ret 1-k carbonators and Z is a carhonyl or hydroxyl methylene group, a separate optical isomer or a pharmaceutically acceptable acid addition salt thereof. 15. Preparation according to claim 13 or 1! rret hst kenr.erk. that it contains 0.2-200 µg of the compound in a unit dose form. . k-naphthylox: / pineridine derivative ret e 10 2, enter?. hydrogen, halo reen, a straight or far? > T e r e r »1> ~ 'grip ret 1-b carbon atoms, a right or branched chain alkoxr. grip r.et i-u carbon atcr.er. whether a trifluoro-methyl green is hydrogen, a short chain alkyl green or a phenyl short chain, the group is short and alkyl green is a straight or branched chain alkyl green ret 1- 3 is colitisers, or an acid addition thereof. 17. Naphthyloxyciperidine derivative according to claim 1c, ret characterized in that it is hydrogen. The naphthyloxypineridine derivative fullers claim 16 retains the characteristic that it is ethyl or green. A cithyLcxyrireridine derivative or one of claims 1 to 18 retains the characteristic that 0 is hydrogen or halogen. ret the characteristic which is hydrogen 21. The k-naphthyloxyrireridine derivative according to claim 16 retains the characteristic that it is k- (2-naphthyloxy) -pineridine or an acid addition salt thereof. The u-naphthyloxypiperidine derivative according to claim 16, characterized in that it is k- (1-rthaphloxy) -nineridine or an acid addition salt thereof. 23. k-naphthyloxynineridine derivative according to claim 16, characterized in that it h- (2-naphthflxv) -1-lfewi- 1 '' "Bl" * wf -¾ V; 8004147-2c-methyl) piperidine or an acid addiction salt thereof. 2l. 1-Naphthyloxypiperidine derivative according to claim 16, characterized in that it is 1- (1-Naphthyloxy) -1- (phenyl-methyl) piperidine or an acid addition salt thereof. 25. Process for the preparation of a 1 + -naphthyloxypiperidine derivative, characterized in that a compound of formula 1, wherein n is an integer of 2-5.5 hydrogen, halogen, a straight or branched chain alkyl group having 1 to 1 carbon atoms is a straight or branched chain alkoxy green with 10 1-1 carbon atoms or a trifluoromethyl group, hydrogen, halogen, a straight or branched chain alkyl group having 1 to 1 carbon atoms or a straight or branched chain alkoxy green having 1 to 1 carbon atoms and Z is a carbonyl or hydroxymethylation group, a separate optical isomer or a pharmaceutically acceptable acid addition salt thereof is prepared by using (o 1 a) compound of formula 2a alkol with a compound of formula 8, wherein halogen represents chlorine, bromine or iodine ep η, P, and Z have the above meaning, in a suitable solvent in the presence of a base 20 and optionally in the presence of a catalytic amount of potassium iodide for 2l- 5n hours at a temperature of 20-188CZ, or (b) when 7. is a hydroxymethylene green, reduces a compound of formula 1, wherein Z is a carbonyl green, and (c) when a pharmaceutically acceptable salt is desired, compound thus obtained reacts with a pharmaceutically acceptable acid. 26. A process for the preparation of a 1-naphthyloxynineridine derivative, characterized in that a compound of the formula II, wherein P is hydrogen, halogen, a straight or branched chain alkyl group with 1 to 1 carbon atoms, a straight or branched chain alkoxy green with 1 -1 carbon atoms or a trifluoromethyl group and "hydrogen" is a alkyl alkyl or phenyl phenyl (short chain alkyl) green, wherein the short chain alkyl green H 8004147-27 is a straight or branched chain alkyl green with 1-3 carbon atoms, or an acid addition cut thereof, by preparing (a) a β-piperidin salt of formula 5 wherein M + is an alkali metal cation and a short chain alkyl or phenyl (short chain alkyl) group. react with a naphthyl fluoride of formula 6, wherein 3 hydrogen, halogen is a straight or branched chain alkyl moiety having 1 to 1 carbon atoms, a straight or branched chain alkoxy moiety having 1 to 1 carbon atoms or a triflucomethyl group, in the presence of a nclair arrotiscal solution 10 thigh at a temperature of from 0 to the heating temperature of the solvent for 1-2 hours, (t) when 15 is hydrogen, the compound thus obtained, wherein a short chain alkyl or phenyl (short chain alkyl) is "··") group, heat under reflux in the presence of an aprotic solvent and a spear of an acid binding agent - = chlorine formic ester, appreciate a carbamate derivative is obtained and the carbamate is cleaved by hydrolysis or reduction and (c) if a salt is desired, the compound thus obtained is reacted with a concentrated acid. 2 -erkwigse according to οο ^ οΙοξ ^ θ 2 ^, characterized in that it is used as a chloroformic ester 2,2,2-trichloroet hv · 1-chloroformate used. 28. bieuwe 1 - n af t hy 1c xy o i p e r i di n e d.e r i v ate as described herein. \ 8004147