SE448728B - 4- (Naphthalene Nylloxy) PIPERIDINE DERIVATIVES AND A PHARMACEUTICAL COMPOSITION WITH ANTIPSYCOTIC EFFECTS - Google Patents

Description

Hydroxymethylene, are useful as antipsychotic agents. These antipsychotic compounds can be prepared from intermediates of formula II H 2 O 11 H 2 where R 2 represents hydrogen, lower alkyl or phenyl (lower alkyl) and where R has previously defined meaning. Compounds of formula II are also novel compounds and are included in the present invention. Also included are pharmaceutically acceptable acid addition salts of the compounds of formulas I and II and individual optical isomers of the compounds of formula I.

Detailed Description of the Invention The compounds of formula I include u% [U- (1- and 2-naphthalenyloxy-1-piperidyl)] - 1-Ä-substituted) phenyl-1-alkanones of formula III HN e I (CH 2) R1 and H- (1- and 2-naphthalenyloxy) -d- (β-substituted) phenyl-1-peridinal channels of formula IV R q IV get OH (6142) n- åH- © -R1 where n, R 8 and R 1 are previously defined, their individual optical isomers and their pharmaceutically acceptable acid addition salts 448 728 In the description, alkyl denotes straight or branched alkyl groups having 1-H carbon atoms, Examples of alkyl groups are methyl, ethyl, propyl and tertiary butyl. refers to straight alkyl chains with 1-3 carbon atoms Alkoxy denotes straight or branched alkoxy chains with 1-H carbon atoms Examples of alkoxy groups are methoxy, ethoxy and isopropoxy Halogen denotes fluorine, chlorine or bromine.

The substituent R may be located at any position in the naphthalene ring system which is not occupied by the (U-piperidyloxy) ~ substituent.

Preferred embodiments of the present invention are compounds of formula I wherein Z represents carbonyl, further preferred embodiments of the invention are n is 3. Further preferred embodiments of the present invention are compounds of formula I wherein R represents hydrogen or halogen. Preferred embodiments of the present invention are also compounds of formula I wherein R 1 represents halogen and especially fluorine.

Examples of compounds of formula I are H- [N- (1-naphthalenyloxy) -1-piperidyl] -1- (U-fluorophenyb-1-butanone, 4- [U- (2-naphthalenyloxy) -1-piperidyl] - 1- (U-fluorophenyl) -1-butanone, N- [U- (6-chloro-2-naphthalenyloxy) -1-piperidyl] -1- (U-fluorophenyl) -1- -butanone, 3- [H- ( 5-methoxy-1-naphthalenyloxy) -1-piperidyl] -1- (H-chlorophenyl) -1- -propanone, 4- [β- (2-naphthalenyloxy) -1-piperidyl] -1- (α-methylphenyl) - 1-butanone, - [H- (1-methyl-2-naphthalenyloxy) -1-piperidyl] -1- (α-ethoxyphenyl) -1- -pentanone, H- [U- (8-methoxy-2-naphthalenyloxy) - 1-piperidyl] -1-phenyl-1-butanone, 6- [U- (5-fluoro-1-naphthalenyloxy) -1-piperidyl] -1- (β-fluorophenyl) -1-hexanone, U- [U - (2-trifluoromethyl-1-naphthalenyloxy) -1-piperidinyl-1- (α-bromophenyl) -1-butanone, H- (1-naphthalenyloxy) -d- (H-fluorophenyl) -1-piperidinbutanol, H- (2-naphthalenyloxy) - & - (H-fluorophenyl) -1-piperidinebutanol, U- (H-trifluoromethyl-2-naphthalenyloxy) -d-phenyl-1-piperidinebutanol, H- (6-bromo-2-naphthalenyloxy) - d- (α-bromophenyl) -1-piperidinepropanol, H- (7-isopropyl-1-naphthalenyloxy) -d- (α-fluorophenyl) -1-piper idin-pentanol, 4- (3-ethoxy-2-naphthalenyloxy) -d- (H-methoxyphenyl) -1-piperidinebutanol, 4- (2-naphthalenyloxy-d- (U-ethylphenyl) -1-piperidinehexanol, U- (8-fluoro-1-naphthalenyloxy) -1- (U-fluorophenyl) -1-piperidinebutanol and 4- (2-methyl-1-naphthalenyloxy) -d- (phenyl) -1-piperidinebutanol.

The invention also includes pharmaceutically acceptable acid addition salts of the compounds of formula I, which are also effective as antipsychotic agents. Suitable salts include those of inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid; carboxylic acids such as acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, dihydroxymaloic acid, 4-benzoic acid; , anthranilic acid, cinnamic acid, salicylic acid, aminosalicylic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid and mandelic acid as well as sulfonic acids such as methanesulfonic acid, 2-hydroxyethanesulfonic acid and p-toluenesulfonic acid.

Novel intermediates for the preparation of the compounds of formula I are compounds of formula II R 1 - II N 2 '2 wherein R has the previously indicated meaning and R 2 represents hydrogen, lower alkyl or phenyl (lower alkyl) and acid addition salts thereof. Preferred compounds are those of formula II wherein R 2 represents hydrogen, methyl or phenylmethyl and those wherein R represents hydrogen or halogen.

Examples of compounds of formula II include the following: 4- (1-naphthalenyloxy) piperidine, N- (2-naphthalenyloxy) piperidine, H- (6-chloro-2-naphthalenyloxy) piperidine, H- (5-methoxy-1-naphthalenyloxy) ) piperidine, of 448 728 U- (1-methyl-2-naphthalenyloxy) piperidine, H- (8-methoxy-2-naphthalenyloxy) piperidine, H- (5-fludro-1-naphthalenyloxy) piperidine, U- (2- trifluoromethyl-1-naphthalenyloxy) piperidine, N- (6-bromo-2-naphthalenyloxy) piperidine, U- (7-isopropyl-1-naphthalenyloxy) piperidine, U- (U-trifluoromethyl-2-naphthalenyloxy) piperidine, H- ( 3-ethoxy-2-naphthalenyloxy) piperidine, H- (8-fluoro-1-naphthalenyloxy) piperidine, H- (2-methyl-1-naphthalenyloxy) piperidine, 1-methyl-4- (1-naphthalenyloxy) piperidine, 1 -methyl-U- (6-chloro-2-naphthalenyloxy) piperidine, 1-methyl-N- (1-methyl-1-naphthalenyloxy) piperidine, 1-methyl-H- (H-trifluoromethyl-2-naphthalenyloxy) piperidine, 1-ethyl-[1- (5-fluoro-1-naphthalenyloxy) piperidine, 1-methyl-[(7-isopropyl-1-naphthalenyloxy) piperidine, 1-propyl-U- (8-methoxy-2-naphthalenyloxy) piperidine, 1- (phenylmethyl) -U- (2-naphthalenyloxy) piperidine, 1- (2-phenylethyl) yl) -H- (5-methoxy-1-naphthalenyloxy) piperidine, 1- (phenylmethyl) -U- (2-trifluoromethyl-1-naphthalenyloxy) piperidine, 1- (phenylmethyl) -U- (6-bromo-2- naphthalenyloxy) piperidine, 1- (phenylmethyl) -H- (3-ethoxy-2-naphthalenyloxy) piperidine, 1- (3-phenylpropyl) -N- (8-fluoro-1-naphthalenyloxy) piperidine and their acid addition salts.

The novel compounds of formula I are antipsychotic agents useful when administered alone or in the form of pharmaceutical preparations containing the novel compounds in combination with a pharmaceutical carrier as neuroleptic sedatives in warm-blooded animals. Neuroleptic sedatives are useful for treating patients showing symptoms of psychosis, such as schizophrenia or severe anxiety, agitation, and aggression. Such agents have a calming effect on the psychomotor activity, induced states of general calmness of the patient without inducing sleep. Patients suitable for treatment with antipsychotic compositions containing the compounds of formula I include warm-blooded animals such as birds, for example parrots, chickens and mammals, such as mice, rats, dogs, cats, horses, pigs, cattle, sheep and humans. Pharmaceutical compositions containing the compounds of formula I may be in solid or liquid form, such as tablets, capsules, powders, solutions, suspensions or emulsions and may be administered orally, parenterally, for example intraperitoneally intramuscularly or subcutaneously; or locally, for example transdermally or transmucosally. The amount constituting an effective amount of the new compounds in unit dose and type and amount of pharmaceutical carrier can vary widely depending on the type of pharmaceutical composition of body weight of members of the patient population to be sedated. The treatment of patients in need of sedatives requires from 0.002 to 100 mg / kg body weight of the patient per day to achieve the desired sedative effect.

For human patients, this sedative effect can be achieved by means of an antipsychotic composition in tablet form containing from 0.2 to 200 mg of active compound and a suitable pharmaceutical carrier taken one to four times daily. Small unit doses are required to achieve comparable neuroleptic effects in animals with less body weight.

The compounds of general formula I may, together with suitable pharmaceutical carriers, be in the form of solid unit dosage forms, such as tablets, capsules and powders, in the form of suppositories or embedded in a polymeric backbone. When preparing solid unit dosage forms, it may be desirable to atomize the compound used. In solid unit dosage forms, the compounds may be combined with conventional carriers, for example, such binders as acacia, corn starch or gelatin, disintegrants such as corn starch, guar gum or alginic acid; lubricants such as stearic acid or magnesium stearate and inert fillers such as lactose, sucrose or corn starch.

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

For liquid preparations, the compounds of formula I may be prepared together with oils, for example fixed oils, such as peanut oil, sesame oil and olive oil; fatty acids such as oleic acid, isostearic acid and fatty acid esters such as isopropyl myristate and fatty acid glycerides; with alcohols such as ethanol, isopropanol and polyethylene glycol, with water or mixtures thereof. Peanut oil and sesame oil are especially useful in the preparation of preparations for intramuscular injection. Oils can also be used in the preparation of soft gelatin formulations and suppositories. Water, common salt, aqueous solutions of dextrose and similar sugars and glycerols, such as polyethylene glycol, can be used to prepare liquid preparations which may suitably contain suspending agents, such as pectin, carbomers, methylcellulose, hydroxypropylcellulose or carboxymethylcelluloses and buffering agents.

For example, when α- [H- (2-naphthalenyloxy) -1- -piperidyl] -1- (U-fluorophenyl) -1-butanone hydrochloride is administered intraperitoneally to mice at a dose of 0.06 mg / kg the total toxicity of d-amphetamine was inhibited to 50% in mice tested according to the procedures described by J. Burn and co-workers Arch. Int. Pharmacodyn. 113, 290-5 (1955), showing the antipsychogenic efficacy, while a dose level of 0.98 mg / kg of the known sedative chlorpromazine is required to achieve a similar response. Similarly, the compounds of the present invention can be shown to have a neuroleptic activity by inhibiting pernicious spasms in mice tested according to the procedure shown by A. Kandel and co-workers Fed. Proc. 19 (1, Pt. 1), 24 (1960).

The neuroleptic activity of these compounds is associated with a reduced tendency to produce extrapyramidal side effects in patients treated with a neuroleptically effective dose compared to known antipsychotics. An indication of the reduced extrapyramidal effect of the compounds of the present invention is obtained when β- [H- (2-naphthalenyloxy) -1- -piperidyl] -1- (U-fluorophenyl) -1-butanone hydrochloride is administered intraperitoneally to mice with a dose of 3Å, 0 mg / kg, which dose was needed to counteract the behavioral effects of apomorphine in 50% of the tested mice according to the general procedure described by PAJ Janssen and employees of Arzneim-Forsch. 10, 1003 Qç fl 448 728 8 (1960), while only 1.4 mg / kg chlorpromazine was required to give a similar effect.

The compounds of formula I are prepared by alkylation of intermediate compounds of formula IIa, R 0 IIa ö N H which represent compounds of formula II, wherein R 2 represents hydrogen and where R has the meaning given above. Compounds of formula IIa were themselves prepared by dealkylation or debenzylation of compounds of formula IIb H 0 IIb R 5 where H 3 represents lower alkyl or phenyl (lower alkyl) and where R has the meaning given above, which represents compounds of formula II, wherein R 2 represents lower alkyl or phenyl (lower alkyl).

Thus, it is apparent that all compounds of formula II are useful intermediates for pharmaceutically useful compounds of formula I. Compounds of formula II are also novel and comprise part of the present invention.

Compounds of formula IIb are prepared by reacting an N-substituted-N-piperidinol salt of formula V if * (wherein N 3 represents lower alkyl or phenyl (lower alkyl) and where M + represents an alkali metal cation, such as potassium, sodium or lithium, with a naphthalene fluoride of formula VI R vi F where R is previously defined, for the preparation of a 1- (lower alkyl) or 1-phenyl (lower alkyl) -U-naphthalenyloxypiperidine of formula IIb Compounds of formula IIa , wherein R 2 represents hydrogen is prepared by dialkylation of N-substituted compounds of formula IIb with the aid of a chloroformic acid ester of the formula O - H RMOC-Cl where Ru represents 2,2,2-trichloroethyl, vinyl, substituted vinyl, benzyl, substituted benzyl or cycloalkyl, which react with the compound of formula IIb in the presence of a proton scavenger, to form a 1- (Ru-oxycarbonyl) -ü- (naphthalenyloxy) -piperidine of formula VII R VII VII 10 = C Ru has the above meaning and removal of The ru- -oxycarbonyl group by means of a weak reducing agent, such as zinc dust in acetic acid or methanol or by acid hydrolysis illustrated by the following reaction scheme: 448 728 than f ° «N. a Û 3 v vl Hb i 'a. g \ 1 R4occ1 R /' reduction R or 0 ¿hydroïys? n Ö vn. Û a N 'N ”H | 0 = C-OR4 Naphthalene fluorides of formula VI are well known or can be prepared in a manner known per se, for example by the procedures described in W. Adcock and co-workers, J. Am. Chem. Soc. 89 (2), 386-390 (1967) and J. Am. cnem. soc. 98 (7), 1701-1711 (1976).

Piperidinol salt of formula V is prepared by reacting the corresponding 1-lower alkyl- or 1-phenyl (lower alkyl) -β-piperidinol with a strong base, such as with an alkali metal hydride, an alkali metal amide or alkyllithium in a manner known per se. way.

The piperidinol salts are 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 point of the solvent for about 1 to about 24 hours. Suitable solvents include tetrahydrofuran, dimethoxyethane, diglyme, dioxane, hexamethylphosphoric triamide, trimethylacetamide, dimethylsulfoxide, 1-methyl-2-pyrrolidone, sulfolane and especially dimethylformamide.

The reaction mixture is cooled and the resulting N-substituted compound of formula IIb or its acid addition salt is isolated in a conventional manner, for example by filtering the reaction mixture and removing the solvent, isolating the product, which is purified by recrystallization and dried. Suitable solvents for the recrystallization are, for example, lower aliphatic alcohols, such as methanol, ethanol and isopropanol; ketones such as acetone and butanone; esters such as ethyl acetate; hydrocarbons such as hexane and combinations thereof. The 1-lower alkyl or 1-phenyl (lower alkyl) -U- (naphthalenyloxy) piperidine of formula IIb thus prepared is then reacted with an ester of chloroformic acid in the presence of an aprotic solvent, and preferably a acid scavenger to form a carbamate of formula VII, which is then cleaved to give the corresponding 1-unsubstituted-H- (naphthalenyloxy) piperidine of formula IIa. Suitable chloroformic acid esters are those which give R 11 -oxycarbonyl substituents which can be hydrolytically cleaved from the nitrogen atom of the compound of formula VII or by reducing conditions under which the naphthalene ring is not hydrogenated. Such chloroformic acid esters include 2,2,2-trichloroethyl ester, which can be cleaved by reduction with zinc powder or by electrolysis; the benzyl ester, the benzyl ester substituted by phenyl, methoxy, methyl, phenylazo, cyano, bromo or chloro, vinyl esters and cycloalkyl esters such as cyclohexyl, cyclopentyl, adamantyl and isobornyl esters which can be cleaved by acid hydrolysis with hydrochloric acids, such as hydrochloric acids and hydrobromic acid or by means of weak acids such as trifluoroacetic acid in suitable solvents. The chloroformic acid esters are suitable for the replacement of alkyl and benzyl substituents in tertiary amines and processes suitable for the cleavage of various Ruoxycarbonyl groups from the nitrogen atom are described by M. Bodanszky and co-workers in Peptide Synthesis second edition p. 21 * 37 (1976) and by R. Olofson et al. In U.S. Pat. No. 3,905,981. The preferred chloroformic acid esters for dealkylation of the compounds of formula II wherein R 2 represents lower alkyl or phenyl (lower alkyl) are 2.2, Suitable solvents for the reaction between an N-substituted compound of formula IIb and 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 and methylene chloride or mixtures thereof. The preferred solvent is methylene chloride. The reaction may be carried out in the presence of a small amount, for example 1-5% by weight of a compound of formula IIb, a proton scavenger, which may be an inorganic base such as sodium or potassium carbonate, a strong organic base such as triethylamine or mixtures thereof. . The reaction mixture is maintained at a temperature between about 0 ° C and the reflux temperature of the solvent from about 1 to about 96 hours. The 1- (Ru-oxycarbonyl) -U- (naphthalenyloxy) piperidine of formula VII thus obtained is isolated, for example in an organic solvent and evaporation of the solvent according to generally known procedures, after which the Ru-oxycarbonyl group is cleaved off in a suitable manner.

In a preferred embodiment of the present invention, an N-lower alkyl or N-phenyl (lower alkyl) -substituted compound of formula IIb is refluxed in methylene chloride with a slight excess, for example from 1.01 to 1.3 equivalents, preferably about 1 1 equivalents of 2,2,2-trichloroethyl chloroformate in the presence of trace amounts of a proton scavenger for from about 6 to about 2H hours at a temperature of from about 15 to about HOOC, preferably at room temperature.

The product was extracted into ether, washed with dilute acid and concentrated in vacuo. The resulting 1- (2,2,2-trichloroethoxycarbonyl) -H- (naphthalenyloxy) piperidine was dissolved in a solvent selected from acetic acid, aqueous solution of acetic acid, a lower alkanol such as methanol, an aqueous solution of lower alkanol and preferably a mixture of acetic acid, water and an ether such as tetrahydrofuran. At a temperature of from about 0 to about 5000, preferably room temperature, 1-5 equivalents, preferably 2 equivalents of zinc powder were added gradually with stirring and the reaction was allowed to proceed from about 1 to about 6 hours until gas evolution ceased. The solvent was evaporated and the N-unsubstituted compound of formula IIa was separated from the remaining zinc salts by basification, extracted into an organic solvent, washed to remove water-soluble impurities, conversion to a water-soluble acid addition salt, washing with organic solvent to remove organic solvents. impurities and finally the reaction mixture was made basic again. The N- -substituted compound was recrystallized in a conventional manner, preferably in the form of its acid addition salt, from suitable solvents such as lower aliphatic alcohols, ketones, esters and combinations thereof.

The free bases of formula II, prepared by the above process, can be converted into acid addition salts by reaction with a suitable acid according to generally known procedures. 1; The compounds of formula I are prepared by reacting the piperidine derivative of formula IIa, where RE represents hydrogen, with a slight excess of a -haloalkyl-phenyl-ketone or a--halo-1-phenyl-1-alkanol with structure VIII in the presence of an excess of an acid acceptor, such as sodium bicarbonate, potassium bicarbonate, sodium carbonate or potassium carbonate and, if desired, a small amount of potassium iodide in a suitable solvent.

If desired, two or more equivalents of the piperidine derivative of formula II may be used relative to compound VIII instead of the mineral acid acceptor. The compounds of formula I may also be prepared from the acid addition salt ° of the compound of formula IIa by reacting the acid addition salt with a compound of structure VIII in the presence of at least two equivalents of the mineral base acceptor. The reaction mixture can react within a wide temperature range. Usually a reaction temperature of from about 20 to 180 ° C is used. The reaction is carried out for a period of time from 1 to N days, during which time all evolved water is collected. Examples of suitable solvents for this reaction include 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 in a conventional manner, for example by allowing the reaction mixture to be filtered and the solvent removed, after which the product is isolated. Alternatively, the filtrate may be treated with a post-solution of a suitable mineral acid or organic acid to obtain the corresponding salt of the product. The crude product is filtered off, purified by recrystallization and dried. Suitable solvents for the recrystallization are, for example, lower aliphatic alcohols, such as methanol, ethane and isopropanol; ketones such as acetone and butanone; nitriles, such as acetonitrile and combinations thereof.

The general procedure for the preparation of compounds of formula I can be represented by the following reaction scheme 448 728 1 * VIII _ Q + - haxs- (cuz) n-z__R1 __b_ @ ¿_ | Ia Et] 'I' HR 0 (5 e »I where n, R, R 1 and Z are previously defined and where halo represents halogen, such as bromine, chlorine or iodine.

The compounds of formula VIII are commercially available or can be manufactured in a manner known per se. The compounds of formula VIII wherein Z represents C = O can be prepared, for example, by reacting a suitable (C-haloalkanoyl halide with a (substituted) broom in the presence of a Lewis acid, such as aluminum chloride or by an (H-substituted) -phenyl-Grignard- reagent is reacted with a suitable (U-haloalkylnitrile. Compounds of formula VIII, where Z represents CHOH can be prepared by reduction by chemical reducing agents or catalytic hydrogenation of the corresponding 1- (U-substituted) phenyl1% D-haloalkanones of formula VIII prepared as described above or by reacting an (H-substituted) phenyl-Grignard reagent with a suitable (3-haloalkanaldehyde.

- (U-naphthalenyloxy-1-piperidyl) -1-phenylpropanones, compounds of formula III, where n is equal to 2, can also be prepared by compounds of formula II; where R 2 represents hydrogen, may react with an appropriate acetophenone and formaldehyde. 1H- (naphthylenyloxy) -1-piperidinealkanols of formula IV can be prepared by reduction of alkanones of formula III. Suitable methods for reducing ketones to alcohols are well known and include catalytic hydrogenation and reduction with chemical 448,728 reducing agents.

For catalytic reduction, a ketone of formula III may be dissolved, for example, in a solvent such as acetic acid, ethyl acetate or a lower aliphatic alcohol such as methanol or isopropanol after which the solution is stirred in the presence of hydrogen at from about 1 to about H atmospheric pressure and room temperature. i.e. 20-2500 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 can be reduced by reduction with a suitable chemical reducing agent. For example, the ketone can be refluxed in ether for 1-5 hours with a metal hydride, for example lithium aluminum hydride or diborane, or allowed to react for 1 / 2-8 hours at a temperature for a lower aliphatic alcohol solvent such as ethanol or methanol with a metal borohydride such as sodium borohydride. or potassium borohydride to give an alcohol of formula IV. Additional reagents suitable for the reduction of a ketone to an alcohol are known to those skilled in the art.

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

Optical isomers of optically active compounds of formula I may be separated by any suitable solvent. For example, the optical isomers of the compounds of formula I wherein Z represents hydroxymethylene can be separated by using a (+) - or (-) - binaphthylphosphoric acid derivative or a salt of said derivative and an optically active base by the process described by R. Viterbo and co-workers in Tetrahedron Letters ü8, I H61? -20 (1971).

Example 1 U- (2-Naphthalenyloxy) -1- (phenylmethyl) piperidine hydrochloride To a stirred suspension of 1.80 g (37.5 mmol) of pentane 50% sodium hydride dispersion in 50 ml of dry dimethylformamide was added in an argon atmosphere a solution of 4.75 g (25.0 mmol) of 1-phenylmethyl-N-piperidinol in 20 ml of dry dimethylformamide, followed by a solution of 3.83 g (26.2 mmol, 1.05 eq) of 2-fluoronaphthalene in 20 ml of dimethylformamide. The mixture was heated to 75 ° C for 23 hours, cooled, beaten in ice water and extracted twice with ether.

The extracts were washed with water and brine, dried over magnesium sulfate and filtered. The filtrate was treated with HCl / methanol and the resulting H- (2-naphthalenyloxy) -1- (phenylmethyl) piperidine hydrochloride was recrystallized from butanone / methanol. Melting point aha-2Mu ° c.

Example 2 U- (1-Naphthalenyloxy) -1-phenylmethylpiperidine hydrochloride The procedure of Example 1 was followed using 1-fluoronaphthalene instead of 2-fluoronaphthalene, wherein U- (1-naphthalenyloxy) -1- (phenylmethyl) piperidine hydrochloride was obtained with a melting point of 222-22M ° C.

Example 3 N- (5-Methoxy-1-naphthalenyloxy) -1- (phenylmethyl) piperidine hydrochloride The procedure of Example 1 was followed but 5-methoxy-1-fluoronaphthalene was used instead of 2-fluoronaphthalene, where U- (5 - -methoxy-1-naphthalenyloxy) -1- (phenylmethyl) piperidine hydrochloride was obtained.

Example H E- (1-methyl-2-naphthalenyloxy) -1-methylpiperidine hydrochloride The procedure of Example 1 was followed but 1-methyl-2-fluoronaphthalene was used instead of 2-fluoronaphthalene and 1-methyl-H--piperidinol was used instead of 1-phenylmethyl-4-piperidinol to give U- (1-methyl-2-naphthalenyloxy) -1-methylpiperidine hydrochloride.

Example 5 H- (4-Trifluoromethyl-2-naphthalenyloxy) -1-methylpiperidinol hydrochloride The procedure of Example 1 was followed but U-trifluoromethyl-2-fluoronaphthalene was used instead of 2-fluoronaphthalene and 1-methyl-H-piperidinol was used instead. for 1-phenylmethyl-β-piperidinol to give H- (H-trifluoromethyl-2-naphthalenyloxy) -1-methylpiperidine hydrochloride. 27 W 448 728 Bxemgel 6 U- (5-fluoro-1-naphthalenyloxy) -1-ethylpiperidine hydrochloride The procedure of Example 1 was followed but 1,5-difluoronaphthalene was used is: α1ec for 2-fluoronaphthalene and 1-ethyl-1H-piperidinol was used instead of 1-phenylmethyl-U-piperidinol to give H - (5-fluoro-1-naphthalenyloxy) -1-ethylpiperidine hydrochloride.

Example 7 U- (2-naphthalenyloxy) piperidine hydrochloride To a stirred solution of 6U, 6 g (0.2OH mol) of N- (2-naphthalenyloxy) -1-phenylmethylpiperidine in 500 ml of methylene chloride was added 37.0 ml (0 , 268 mol) of 2,2,2-trichloroethyl chloroformate and about 200 mg of potassium carbonate. The mixture is stirred at room temperature for H8 hours and beaten in an amount of ether and water. The organic phase was washed with dilute hydrochloric acid and an aqueous solution of potassium carbonate, dried over magnesium sulphate and concentrated in vacuo.

The resulting 1- (2,2,2-trichloroethoxycarbonyl) -4- (2-naphthylenyloxy) piperidine was dissolved in a mixture of 250 ml of acetic acid, 250 ml of tetrahydrofuran and 125 ml of water. 28.5 g (0.436 mol) of zinc powder were added in small portions with stirring and the exothermic reaction was allowed to proceed for 2 1/2 hours. The mixture was filtered and the solvent was removed in vacuo. The residue was partitioned between ether and an aqueous solution of sodium hydroxide, and the organic phase was washed with water and extracted with dilute aqueous hydrochloric acid. The acidic extracts were washed with ether, basified with sodium hydroxide and extracted into ether and toluene and the organic solution was washed, dried over magnesium sulphate and concentrated in vacuo to give H- (2-naphthalenyloxy) piperidine which was redissolved in ethanol / ether and treated with ethanol / ether. dry HCl and the hydrochloride salt was recrystallized from butanone / methanol. The salt had a melting point of 229.5- -231.5 ° C. Example 8 N- (1-naphthalenyloxy) piperidine hydrochloride in Following the procedure of Example 7 and H- (1-naphthalenyloxy) -1- (phenylmethyl) piperidine used instead of U- (2-naphthalenyloxy) -1 (phenylmethyl) piperidine, Ä- (1-naphthalenyloxy) piperidine hydrochloride is obtained. Example 9 H- (N-trifluoromethyl-2-naphthalenyloxy) piperidine hydrochloride If the procedure of Example 7 was used but U- (N-trifluoromethyl--2-naphthalenyloxy) -1-methylpiperidine was used instead of U- (2 - -naphthalenyloxy-1- (phenylmethyl) -piperidine gives H- (U-trifluoromethyl-2-naphthalenyloxy) piperidine hydrochloride.

Example 10 H- (5-Fluoro-1-naphthalenyloxy) piperidine hydrochloride If the procedure of Example 7 was used and β- (5-fluoro-1-naphthalenyloxy) -1-ethylpiperidine was used instead of β- (2-naphthalenyloxy) ) -1- (phenylmethyl) piperidine N- (5-fluoro-1-naphthalenyloxy) piperidine is obtained.

Example 11 H- (5-Methoxy-1-naphthalenyloxy) piperidine hydrochloride A solution of 18.4 g (50 mmol) of U- (5-methoxy-1-naphthalenyloxy) -1- - (phenylmethyl) piperidine in 10 ml of 1 , 2-Dichloroethane was gradually added to a cooled solution of 65 mmol of vinyl chloroformate in 50 ml of 1,2-dichloroethane and the mixture was stirred at room temperature for U hours and concentrated in vacuo.

The H- (5-methoxy-1-naphthalenyloxy) -1- (vinyloxycarbonyl) piperidine thus obtained was stirred for 2 hours with 2N HCl in methanol to give N- (5-methoxy-1-naphthalenyloxy) piperidine hydrochloride.

Example 12 N- (1-methyl-2-naphthalenyloxy) piperidine hydrochloride If the procedure of Example 11 was used and 4- (1-methyl-2-naphthalenyloxy) -1-methylpiperidine was reacted with benzyl chloroformate, 4- (1 -methyl-2-naphthalenyloxy) -1- (phenylmethoxycarbonyl) piperidine which on hydrolysis gave β- (1-methyl-2-naphthalenyloxy) piperidine hydrochloride.

Example 15 N- [U- (2-naphthalenyloxy) -1-piperidyl] -1-phenyl-1-butanone hydrochloride A solution of 5.67 g (25 mmol) of U- (2-naphthalenyloxy) piperidine, .0 g ( 27.0 mmol) H-chloro-1-phenyl-1-butanone, 0.1 g of potassium iodide and 0.5 g of potassium bicarbonate in 100 ml of toluene were heated for 48 hours and stirred on a steam bath. The mixture was partitioned between 44 ml of methylene chloride / ether and water and the organic phase was dried over magnesium sulphate. A solution with an excess of HCl in ether was added and the resulting precipitate was recrystallized from methanol / butanone to give - (2-naphthalenyloxy-1-piperidyl) -1-phenyl-1-butanone hydrochloride.

Example 1a H- [4- (2-Naphthalenyloxy) -1-piperidyl] -1- (U-fluorophenyl) -1-butanone hydrochloride The procedure of Example 13 was followed but U-chloro-1- (U-fluorophenyl) ) -1-butanone was used instead of U-chloro-1-phenyl-1-butanone to give U- [H- (2-naphthalenyloxy) -1-piperidyl] -1- (U-fluorophenyl) -1-butanone hydrochloride, m.p. 219-221.5 ° C.

Example 15 4- [H- (1-naphthalenyloxy) -1-piperidyl] -1- (H-fluorophenyl) -1-butanone hydrochloride If the procedure of Example 13 was followed but U-chloro-1- (U-fluorophenyl) phenyl) -1-butanone was used instead of 4-chloro-1-phenyl-1-butanone and U- (1-naphthalenyloxy) piperidine hydrochloride was used instead of H- (2-naphthalenyloxy) piperidine hydrochloride was obtained H- [U- (1-naphthalenyloxy) -1-piperidyl] -1- (α-fluorophenyl) -1-butanone hydrochloride having a melting point of 220-222.5 ° C.

Example 16 3- [H- (5-Methoxy-1-naphthalenyloxy) -1-piperidyl] -1- (H-chlorophenyl) -1-: propanone hydrochloride If the procedure of Example 13 was followed but N- (5-methoxy -1- -naphthalenyloxy) piperidine hydrochloride was used instead of U- (2-naphthalenyloxy) piperidine hydrochloride and 3-chloro-1- (U-chlorophenyl) -1-propanone was used instead of U-chloro-1-phenyl -1-butanone gave 5-EU- (5-methoxy-1-naphthalenyloxy) -1-piperidyl] -1- (U-chlorophenyl) -1-propanone hydrochloride.

Example 17 - [H- (2-Naphthalenyloxy) -1-piperidyl] -1- (H-methylphenyl) -1-pentanone hydrochloride If the procedure of Example 13 was followed but 5-chloro-1- (U-methylphenyl) - -1-pentanone was used instead of H-chloro-1-phenylel-butanone to give 5- [N- (2-naphthalenyloxy-1-piperidyl] -1- (H-methylphenyl) -1-pentanone hydrochloride. 448 728 Example 18 4- [N- (1-methyl-2-naphthalenyloxy) -1-piperidyl] -1- (N-fluorophenyl) -1- -butanone '1' A solution of 3.47 g (12 , 5 mmol) Ä- (1-methyl-2-naphthalenyloxy) -piperidine, 2.63 g (13.1 mmol) H-chloro-1- (H-fluorophenyl) -1-butanone,, 2 g (52 mmol ) potassium bicarbonate and a knife-edged potassium iodide in 60 ml of toluene were heated to reflux for 80 hours The mixture was partitioned between toluene and water and the organic phase was washed with brine, dried over magnesium sulphate and concentrated in vacuo to give U- [U- (1- methyl-2-naphthalenyloxy) -1-piperidyl] -1- (H-fluorophenyl) -1-butanone.

Example 19 6- [H- (H-trifluoromethyl-2-naphthalenyloxy) -1-piperidyl] -1- (β-methoxyphenyl) -1-hexanone If the procedure of Example 18 was followed but U- (H-trifluoromethyl- 2-naphthalenyloxy) piperidine was used instead of U- (1-methyl-2-naphthalenyloxy) piperidine and 6-bromo-1- (U-methoxyphenyl) -1-hexanone was used instead of N-chloro-1- (U- fluorophenyl) -1-butanone to give 6- [4- (4-trifluoromethyl-2-naphthalenyloxy) -1-piperidyl] -1- - (α-methoxyphenyl) -1-hexanone.

Example 20 d- (U-fluorophenyl) -N- (1-methyl-2-naphthalenyloxy) -1-piperidinebutanol If the procedure of Example 18 was followed and 4-chloro-1- (β-fluorophenyl) butanol was used instead of Echloro -1- (H-fluorophenyl) -1- -butanone, then ok (U-fluorophenyl) -4- (1-methyl-2-naphthalenyloxy) -1-piperidinebutanol is obtained.

Example 21 d-Phenyl-H- (5-fluoro-1-naphthalenyloxy) -1-piperidinepropanol If the procedure of Example 18 was used and H- (5-fluoro-1-naphthalenyloxy) piperidine was used instead of (1-methyl-2 - -naphthalenyloxy) piperidine and 3-bromo-1-phenyl-propanol instead of Ä-chloro-1- (H-fluorophenyl) -1-butanone to give d-phenyl-β- (5-fluoro-1-naphthalenyloxy) -1-piperidinepropanol.

Example 22 3- [H- (5-Methoxy-1-naphthalenyloxy) -1-piperidyl] -1- (β-fluorophenyl) -1-propanone 471 nl's 21 448 728 A mixture of 25.5 g (0 , 1 mol) U- (5-methoxy-1-naphthalenyloxy) -piperidine, 9 g (0.3 mol) of paraformaldehyde and 13.8 g (0.1 mol) of H'-fluoroacetophenone in 100 ml of isopropyl alcohol containing 2 drops concentrated hydrochloric acid was boiled under reflux for 2 hours. The mixture was filtered and the filtrate was concentrated to about 100 ml and cooled. The resulting precipitate was recrystallized from ethanol to give 3- [H- (5-methyl-1-naphthalenyloxy) piperidylP1- (4-fluorophenyl) -1-propanone.

Example 23 df (H-fluorophenyl) -H- (2-naphthalenyloxy) -1-piperidinebutanol To 8.0 g (0, 20 mol) of u- [1z- (z-naphthalenyloxy) -1-piperidyl] -1- (U-fluorophenyl) -1-butanone in HCl in 50 ml of methanol was added 1.1 g (0.02 mol) of sodium methoxide and then 2.7 g (0.05 mol) of potassium borohydride and the mixture was stirred at room temperature for 2 hours.

The methanol was removed under reduced pressure on a steam bath and then 50 ml of 10% sodium hydroxide solution was added. The mixture was stirred for 15 minutes and 100 ml of chloroform was added. Stirring was continued for 1/2 hour. The chloroform phase was separated and combined with two 25 ml chloroform extracts from the aqueous phase, washed with water and brine, dried over magnesium sulfate, filtered and concentrated to a solid. The solid was recrystallized from ethanol / water to give d- (U-fluorophenyl) -β- (2-naphthalenyloxy) -1-piperidinebutanol.

Example 2U d- (4-Methoxyphenyl) -ü- (H-trifluoromethyl-2-naphthalenyloxy) -1-piperidinehexanol When in the procedure of Example 23 6- [U- (U-trifluoromethyl-2-naphthalenyloxy) -1 -piperidyl] -1- (N-methoxyphenyl) -1-hexanone hydrochloride was used instead of N- [N- (2-naphthalenyloxy) -1-piperidyl] -1- (U-fluorophenyl) -1-butanone is obtained d- (U-methoxyphenyl) -U- (U-trifluoromethyl-1-naphthalenyloxy) -1-piperidinehexanol.

Example 25 Tablet preparation A representative tablet preparation containing active compound of the present invention is as follows: Per tablet (a) 4 - [(2-naphthalenyloxy) -1-piperidyl] -1- (H-fluorophenyl) -1-butanone hydrochloride 25.0 mg (b) Wheat starch 3.5 mg (c) Lactose 10.0 mg (d) Magnesium stearate 0.5 mg Granulation was obtained in a mixture of lactose with starch after which the granulated starch paste was dried, sieved and mixed with the active ingredient and magnesium stearate.

The mixture was beaten into tablets weighing 39.0 mg each.

Example 26 Gelatin capsule preparation Composition for hard gelatin capsules as follows: (a) U- [α- (2-naphthalenyloxy) -1-piperidyl] -1- (H-fluorophenyl) -1-butanone hydrochloride (b) Talc 5 (c) Lactose 100 The preparation was prepared by passing the dry powders of (a) and (b) through a fine sieve and mixing well.

The powder was then filled into hard gelatin capsules in an amount of 115 mg per capsule.

Example 27 Injectable Suspension Preparation An injectable suspension is as follows: 1 ml ampoules for intramuscular injection.

Weight (a) H- [H- (2-naphthalenyloxy) -1-piperidyl] -1- (4-fluorophenyl) -1-butanone (particle size (10 μm) - 1.0 (b) Polyvinylpyrrolidone (molecular weight 25000) 0.5 (c) Lecithin 0.25 (d) Water for injection 100.0 448 728 The materials (a) - (d) were mixed, homogenized and filled into 1 ml ampoules which were sealed and autoclaved for 20 minutes at 12100. Each vial contained 10 mg per ml of the new compound (a) 448 728 24 Comparative Sample Sample A: Antagonism against D-amphetamine-induced lethality in constricted mice ß A group of 15 male Swiss mice obtained from Laboratory Supply was placed in an accessible plastic mouse cage (approximate dimensions 29 x 18 x 13 cm) partially filled with a layer of sawdust.

Steel wire mesh was used to pour the animals into the cage. Free access to food and water was allowed. The room temperature during the experiment was kept as close as possible to 22 ° C.

The animals were treated with the test compound and at a selected time thereafter they were treated with d-amphetamine sulphate, 9.0 mg / kg intraperitoneally. prepared as a solution in distilled water so that a dose of 10 mg / kg was the required dose.

The approximate number of live animals in each group was counted 18 hours after amphetamine administration.

The dose of the test compound that provided protection against amphetamine-induced lethality in 50% of the test animals (ED50) was calculated using a sub-data analysis program.

A dose of 9.0 mg / kg d-amphetamine sulphate intraperitoneally regularly results in 80 to 100 2 mortality in the control groups. Antipsychotics, which are specific inhibitors of this effect. exerts its activity at doses well below those that cause obvious effects in mice.

Sample B: Inhibition of apomorphine-induced stereotype in rats Male rats weighing between 100 and 300 g. Obtained for use from Laboratory Supply (Sprague-Dawley colonies). held individually in cages with galvanized steel walls with, 1.2 cm opening in 5 in a row lined cells with a size of G .24 x 15.24 x 15.24 cm. Each cell was equipped with a snap cap. 448 728 All drugs and vehicle controls were injected at doses including a standard volume of 1.0 ml / kg. The standard agonist apomorphine hydrochloride was prepared as a solution in distilled water containing 0.1 t of ascorbic acid to prevent oxidation. The test compound was prepared as a solution or kept as a suspension with Tween 80 in distilled water. Injections of the test compound were given intraperitoneally and the apomorphine hydrochloride was injected subcutaneously.

The rats were injected with a certain dose of the test compound. then at appropriate intervals of 1.0 mg / kg apomorphine hydrochloride and returned to their cages. Observation of apomorphine stereotopia began 15 minutes after the apomorphine injection and continued for a period of 3 minutes. The answer that was recorded and judged regarding the degree and frequency consisted of sniffing, licking or chewing. increase and exploration. Continuous and excessive sniffing with the nose through a hole in the cage wall differs from normal breathing behavior. Chewing and licking activity occurred for no apparent reason.

Rising and searching as standing upright on the hind paws and the head raised backwards and the nose stuck in a space in the cage wall were not observed in normal untreated rats.

Ascension without search is an incomplete maneuver that was rarely observed and therefore not recorded.

In determining the median dose of a selected compound that inhibits apomorphine (ED50), measured doses were administered to a group of rats and the number of rats showing significant inhibition of apomorphine was recorded for each group.

ED5d data are obtained by data processing a Berkson dose-effect analysis. Inhibition of this behavior has previously been associated with clinical antipsychotic activity. but it has been shown to reflect extrapyramidal susceptibility of the test compounds rather than beneficial antipsychotic effect. The table shows the structure of the tested compounds as well as the chemical names for them. n al microns al uocwmß al dæum ^ HwwHumm «M1N | HMuwE | z. | Nl¶ | OP | 0ummxuwEHwumE | N w fl uo al MonwæslcocwwOnæu al nßlon f w f umm al etc. xon al mnnvnA al æcmwouo al xam. | N¶ | w | 0uo al Hw | .v w fl uoHxo ~ w> g | ao = m» ON | P | .H> = w «OHo = H« | «. | _W ^ H> w fl ~ mm fi m | _ | fi xo = ww |« .fw w fl uoHxø »ø> n | = o = m ~ øn | _ | A fi wawwouos fl wnq. | ~ 1ß | fi> ø fl ~ wm fi m «P |. fl xo fi wcm fi mpwmcuvv |« | w | «w fl uoaxouw> s | conmuøn | ~ | A fi æcmwouøsamlw.1« | ß | HæU fl Hwm fl m | P | _ fl xoHæcm fi mummc U nH mH. www> Nm m.o | wc fl nmw fl uo fl sa M ooowlooow or o ~ N m.o oowloom aOU fl Hmm0amm oN «| ow mf P.NN« ß_F oomloop x flfl xmu Unwx wumw fl w fl »um flfl acw nmmc fl nmumm omm? A omm A Qom A ow ~ o cow A «.w ~ una ooom fi iooßw ommr A om A mo_o ooæloov mc fl cz fl umms oo .fi wuww pm fifl 04: cm ummc fl cmumm 7 / OO 4 \ Q <\ m Amv Em fl commumm Amy Em fl mucm m mw uc m flfi commucm A ln fl wuøëomd i flfl šmnwmäá A% a fi mnmü 1

Claims (4)

1 '448 728 18.4.1984 Patent Claim A compound of the formula "lo LJN] '_ _ / \ _ (c fl yn z 111 R" v 5 Å where n represents 2, 3. 4 or 5: where R represents hydrogen. Halogen, straight or branched alkyl chains with 1 Straight or branched alkoxy chains having 1-4 carbon atoms or trifluoromethyl, wherein R 1 represents hydrogen, halogen, straight or branched alkyl chains having 1-4 carbon atoms, straight or branched alkoxy chains having 1-4 carbon atoms and where Z represents carbonyl or hydroxymethylene, and individual optical isomers or pharmaceutically acceptable acid addition salts thereof. Compound according to Claim 1, characterized in that it consists of 4- [N- (2-naphthalenyloxy) -1-piperidyl] -1- (4-fluorophenyl) -1-butanone or pharmaceutically acceptable acid addition salts hence. Compound according to Claim 1, characterized in that it consists of 4-13- (1-naphthalenyloxy) -1-piperidyl] -1- (4-fluorophenyl) -1-butanone or a pharmaceutically acceptable acid addition salt. hence. 4. Pharmaceutical composition with antipsychotic effect. k n n - n e t e c k n a d in that it consists of a compound according to claim 1 and a pharmaceutical carrier.