DK150477B - ANALOGY PROCEDURE FOR PREPARING 4- (4- (NAPHTHALENYLOXY) -1-PIPERIDINYL) -1-PHENYL-1-BUTANON DERIVATIVES AND INTERMEDIATES FOR THE USE OF THE PROCEDURE - Google Patents

Description

in 150477 o

The present invention relates to an analogous process for the preparation of novel 4- [4- (naphthalenyloxy) -1-piperidinyl] -1-phenyl-1-butanone derivatives of the general formula set forth in claim 1, which derivatives are useful neuroleptic tranquilizers. agents whose use does not cause significant extrapyramidal side effects. The invention relates to the novel 4-naphthalenyloxypiperidines of formula II as claimed in claim 1 for use as chemical intermediates in said analogous method, which is unique in the characterizing part of claim 1.

1-Phenyl-β- (1-piperidyl) alkanones are an important class of central nervous system depressants. Various compounds of this type are known, cf. eg. U.S. Patent Nos. 3,428,991, 3,518,276, 3,576,810, 3,816,433, 3,888,867 and 3,907,812. Although compounds of this type have often been found to have potent antipsychotic activity, their use has been limited due to the presence of severe extrapyramidal side effects and transient hypotension.

From US Patent No. 3,743,645, 1-substituted 4-phenoxypiperidines of formula I 2 are known, the most closely related to the compounds of this invention being the 1- [3- (4-30- fluorobenzoyl) propyl] -4- (2-methoxyphenoxy) -piperidine, which is reported to have a sedative effect as tested by JP de Vanzo et al. described in Psychopharcologia 9, 210 (1966), by effectively blocking aggressive behavior in warring mice when administered at doses of 5-35-20 mg / kg intraperitoneally. According to U.S. Pat.

2

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The synthesis route \ χΟΗ 1 \ H2 Pd / C ^ is used

X ./ \ A X_X

u 1 kX O

Y R2 Y

10 -p H o. - x ^ = ^ 1 1 "" 1

o ^ V

15 H

It has now been found that the novel ω- (4-naphthalenyloxy-1-piperidyl) -1-phenylbutanones prepared by the process of the invention exhibit a stronger antipsychotic activity than the corresponding phenoxy compounds without causing significant extrapyramidal side effects and with only little effect on blood pressure. At the same time, they are far less toxic and do not have neuromotor side effects that have traditionally accompanied treatment with the 25 conventional antipsychotic agents.

The present compounds have the formula 30

'I

LbJ o ™ 2X-y3'R1 35 '—1

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3 is hydrogen or halogen. These compounds are prepared analogously to the last step of the above method from intermediates of the formula 5 kJUi b n

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10

H

Compounds of formula II are also unknown compounds and form part of the present invention. Acid addition salts of compounds of formulas I and II can be prepared.

Compounds of formula I include [4- (1- and 2- naphthalenyloxy-1-piperidyl] -1- (4-substituted) phenyl-1-butanones and their pharmaceutically acceptable acid addition salts.

Where R 1 is halogen, it is especially fluorine.

By the process of the invention, pharmaceutically acceptable acid addition salts can also be prepared from the compounds of formula I which are also active 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, citric acid, citric acid. acid, hydroxymaleic acid, dihydroxymaleic acid, benzoic acid, phenylacetic acid, 4-aminobenzoic acid, 4-hydroxybenzoic acid, anthranilic acid, cinnamic acid, salicylic acid, amino salicylic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid and methanolic acid, -hydroxyethanesulfonic acid and p-toluenesulfonic acid.

The aforementioned novel compounds of formula I are antipsychotic agents which are useful when administered alone or in the form of pharmaceutical preparations containing the active compounds combined with a pharmaceutical carrier as neuroleptic tranquilizers for heat treatment. 5 bloodied animals. Neuroleptic tranquilizers are useful in treating patients who exhibit symptoms of psychoses such as schizophrenia or severe anxiety, arousal or aggression. Such agents have a sedative effect on psychomotor activity and cause a state of general calm in the patient without causing sleep. Patients suitable for treatment with antipsychotic agents containing compounds of formula I include warm-blooded animals such as birds, e.g. turkeys and chickens, and mammals, e.g. mice, rats, dogs, cats, horses, pigs, cattle, sheep and humans-15 happen.

Pharmaceutical compositions containing compounds of formula I may be in solid or liquid form, such as tablets, capsules, powders, solutions, suspensions or emulsions, and may be administered orally, parenterally, e.g. intraperitoneally, intramuscularly or subcutaneously or topically, e.g. transdermally or transmucosally. The amount constituting an effective quantity of the novel compounds obtained with a unit dosage, as well as the nature and quantity of the pharmaceutical carrier, varies within wide limits according to the type of pharmaceutical preparation and the body weight of the patients to be treated. . Treatment of a patient in need of sedatives involves from 0.002 to 100 mg / kg of body weight per patient. day to achieve the desired sedative effect. For humans, this degree of sedation can be achieved by an antipsychotic in the form of tablets containing from 0.2 to 200 mg of active compound and an appropriate pharmaceutical carrier taken 1-4 times daily. Small unit dosage forms will be required to achieve a comparable neuroleptic effect on smaller animal species.

5 150477 0 When e.g. 4- [4- (2-naphthalenyloxy) -1-piperidyl] -1- (4-fluorophenyl) -1-butanone hydrochloride is administered intraperitoneally to mice at a dose of 0.06 mg / kg, the total inhibition toxicity of d-amphetamine in 50% of mice tested i-5 following the methods described by J. Burn et al. in Arch. Int. Pharmacodyn. 113, 290-5 (1955), thus showing antipsychotic efficacy, whereas a dose level of 0.98 mg / kg of the known sedative chlorpromazine is required to achieve a similar reaction level. Similarly, the compounds prepared by the method of the invention exhibit neuroleptic activity in inhibiting harmful polishing in mice by the method described by A. Kandel et al. in the Fed. Proc., 19, (1, pt. 1), 24 (1960).

The neuroleptic efficacy of the subject compounds is accompanied by a diminished tendency for extrapyramidal side effects in patients treated with a neuroleptically effective dose, compared to known antipsychotic agents. As evidence of the reduced extra-pyramidal effect of the compounds, when 4-20 [4- (2-naphthalenyloxy) -1-piperidinyl] -1- (4-fluorophenyl) -1- -butanone hydrochloride is administered intraperitoneally to mice, a dose of 34.0 mg / kg to counteract the effects of apomorphine on the behavior of 50% of mice tested using the method referred to by PAJ Janssen et al. in Arz-25 neim-Forsch. 10, 1003 (1960), whereas only 1.4 mg / kg of chlorpromazine is required to achieve a similar effect.

Compounds of formula X are prepared by alkylation of the intermediate compounds of formula II.

CO

? island

H

35

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6 150477 prepared by dealkylation or debenzylation of compounds of formula IIb 5 OQo iib 6 '

Ra 10 is lower alkyl or phenylalkyl, especially benzyl.

Compounds of formula IIb are prepared by reacting an N-substituted-4-piperidinol salt of formula 0 "M +" ό 1

R 5 wherein R 3 is lower alkyl or phenylalkyl and M + is an alkali metal cation such as potassium, sodium or lithium, with a naphthalene fluoride of formula 00

25 F

for the preparation of a 1-alkyl or 1-phenylalkyl-4-naphthalenyloxypiperidine of formula IIb. The compounds of formula II are prepared by dealkylation or debenzylation of N-substituted compounds of formula IIb by means of a chloroformic acid ester of formula R RO-C1 wherein R ^ is 2,2,2 - trichloroethyl, vinyl, substituted vinyl, benzyl, substituted benzyl or cycloalkyl reacted with the compound of formula IIb in the presence of a proton-removing reaction.

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No. 7 150477 to prepare a 1- (R 2 -oxycarbonyl) -4- (naphthalenyloxy) piperidine of the formula

I VII

9 = c-o-r4 10 where has the meaning set forth above, and by removing the R 2 -oxycarbonyl group by a mild reducing agent such as zinc dust in acetic acid or methanol or by acid hydrolysis as illustrated in the reaction scheme below.

15 -o * + OQ, OQ

rS F ΐ.

V O

20 w VI 11 b i1 V R3 o reduction ^^

CM or CM

0 hydrolysis® "9" 9 H 0 = C-OR4 30

The naphthalene fluorides of formula VI are known and can be prepared by known methods, e.g. as described by W. Adcock et al. in J. Am. Chem. Soc. 89 (2), 386-390 (1967) and 35 in j. Am. Chem. Soc. 98 (7), 1701-1711 (1976).

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8 150477

Piperidinol salts of Formula V are prepared by reacting the corresponding 1-lower alkyl or 1-phenylalkyl-4-piperidinol with a strong base such as an alkali metal hydride, an alkali metal amide or alkyl lithium by conventional methods. The piperidinol salt is reacted with the naphthalene fluoride of formula VI in the presence of a polar aprotic solvent at a temperature of from ca. 50 to approx. 200 ° C or at the boiling point of the solvent for approx. 1 to approx. 24 hours. Suitable solvents include tetrahydrofuran, dimethoxyethane, diglyme, dioxane, hexamethylphosphoric triamide, dimethylacetamide, dimethylsulfoxide, 1-methyl-2-pyrolidone, sulfolane and especially dimethylformamide.

The reaction is cooled and the resulting N-substituted compound of formula IIb or its acid addition salt is isolated by conventional means, e.g. For example, the reaction mixture can be filtered and the solvent removed, the product isolated and purified by recrystallization and dried. Suitable solvents for recrystallization are e.g. 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- phenylalkyl-4- (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 an acid-removing agent to form a carbamate of formula VII which is then cleaved to give the corresponding 1-unsubstituted-4- (naphthalenyloxy) piperidine of formula II. Suitable chloroformic acid esters are those which give R 2 -oxycarbonyl substituents which can be cleaved from the nitrogen atom in connection with Formula VII hydrolytically or under such reducing conditions that the naphthalene ring is not hydrogenated. Such chloric formic esters include the 2,2,2-trichloroethyl ester which can be cleaved by reduction with zinc dust or by electrolysis; benzyl ester, benzyl esters substituted with phenyl, methoxy, methyl, phenyl

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Azo, cyano, bromine or chlorine, vinyl esters and cycloalkyl esters such as cyclohexyl, cyclopentyl, adamantyl and isobornyl esters which can be cleaved by acid hydrolysis with strong acids such as hydrochloric or hydrochloric acid or by weak acids such as trifluoroacetic acid , in appropriate solvents. Chloromyric acid esters suitable for rearranging alkyl and benzyl substituents from tertiary amines and methods suitable for cleavage of the various R 2 -oxycarbonyl groups from the nitrogen atoms are described by M-Bodanszky et al. in Peptide ΊΟ Synthesis, 2nd ed. (John Wiley & Sons), pages 21-35 (1976) and by R. Olofson et al. in U.S. Patent No. 3,905,981. The preferred chloroformic acid ester for dealkylation of compounds of formula II wherein R 2 is lower alkyl or phenyl (lower alkyl) is 2,2,2-trichloroethyl chloroformate.

Suitable solvents for the reaction between an N-substituted compound of formula IIb and a chloroformic acid ester are aprotic organic solvents, e.g. ethers such as diethyl ether and tetrahydrofuran, aromatic hydrocarbons such as toluene and benzene, chlorinated hydrocarbons such as toluene and benzene, chlorinated hydrocarbons such as chloroform, dichloroethane and methylene chloride or mixtures thereof.

The preferred solvent is methylene chloride. The reaction may be carried out in the presence of a small amount, e.g. 1-5% by weight of the amount of compound of formula IIb, of a proton scavenger, which may be an inorganic base such as sodium or potassium carbonate, a strong organic base such as triethylamine or a mixture thereof. The reaction mixture is kept at a temperature between ca. 0 ° C and the reflux temperature of the solvent for approx. 1 to approx. 96 hours. The 1- (R 2 -oxycarbonyl) -4- (naphthalenyloxy) piperidine of formula VII thus prepared is isolated, e.g. by extraction in an organic solvent and evaporation of the solvent by conventional methods and the R4-oxycarbonyl group is decomposed by a suitable method.

In a preferred embodiment, a N-lower alkyl or N-phenylalkyl-substituted compound of formula IIb in methylene chloride is refluxed with a small excess, e.g. from 1.01 to 1.3 equivalents, preferably approx. 1.1 equivalents, 2,2,2-trichloroethyl chloroformate in the presence of a trace-5 amount of a proton-removing reagent for from ca. 6 to approx. 24 hours at a temperature of from approx. 15 to approx. 40 ° C, preferably at room temperature. The product is extracted into ether, washed with dilute acid and evaporated in vacuo. The resulting 1- (2,2,2-trichloroethoxycarbonyl) -4- (naphthalenyloxy) piperidine 10 is dissolved in a solvent which is acetic acid, aqueous acetic acid, a lower alkanol such as methanol, an aqueous lower alkanol, or preferably a mixture of acetic acid. , water and an ether such as tetrahydrofuran. At a temperature of approx.

0 to 50 ° C, preferably at room temperature, is preferably added at approx. 2 equivalents of zinc dust gradually with stirring, and the reaction is allowed to proceed for approx. 1 to approx. 6 hours until gas evolution ceases. The solvents are evaporated and the N-unsubstituted compound of formula II is separated from the remaining zinc salts by basification, extraction in an organic solvent, washing to remove water-soluble impurities, conversion to a water-soluble acid addition salt, washing with organic solvents to remove organic solvents. and rebasification. The N-unsubstituted compound is recrystallized by conventional methods, preferably in the form of its acid addition salt, from suitable solvents such as lower aliphatic alcohols, ketones, esters and combinations thereof.

Free bases of formula II prepared by the above method can be converted to acid addition salts by reaction with a suitable acid according to generally known methods.

The compounds of formula I are prepared by reacting a piperidine derivative of formula II with a small o-offset of a structure VIII-haloalkylphenyl ketone

In the presence of an excess of an acid acceptor such as e.g.

Sodium bicarbonate, potassium bicarbonate, sodium carbonate or potassium carbonate, and optionally a small amount of potassium iodide, in a suitable solvent. If desired, two or more equivalents of the piperidine derivative of formula II relative to compound VIII may be used instead of the mineral base as an acid acceptor. The compounds of formula I may also be prepared from the acid addition salt of the compound of formula II by reacting the acid addition salt with a compound of structure VIII in the presence of at least two equivalents of the mineral base as an acid acceptor. The reaction mixture can be reacted over a large temperature range. As a rule, a reaction temperature of from ca. 20 to 180 ° C. The reaction takes place over a period of from 1 to 4 days, during which time all produced water can be collected. Examples of suitable solvents for this reaction include toluene, xylene, chlorobenzene, methylisobutyl ketone and lower aliphatic alcohols such as ethanol, propanol and butanol.

When the reaction is complete, the product is isolated in the usual way, e.g. For example, the reaction mixture can be filtered and the solvent removed, isolating the product. Alternatively, the filtrate may be treated with an ethereal solution of a suitable mineral or organic acid to give the corresponding salt of the product. The crude product is filtered off, purified by recrystallization and dried. Suitable solvents for recrystallization are e.g. lower aliphatic alcohols such as methanol, ethanol and isopropanol, ketones such as acetone and butanone, nitriles such as acetonitrile and combinations thereof.

The general process for preparing 30 compounds of formula I can be reproduced by the following reaction scheme.

35 t50477

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12 OQ o 0 + halo- (CHa) 3-C- ^ J-Rx ~ ..hase

µ 6 VIII

H

and 10 o ό 4- I o (CHa) 3-C-Q-ftx 15 where has the meaning given above and halo is a reactive halogen such as bromine, chlorine or iodine.

Compounds of formula VIII are commercially available or may be prepared by known methods. Compounds of formula VIII can, e.g. is prepared by reacting an appropriate G) -haloalkanoyl halide and a (substituted) benzene in the presence of a Lewis acid such as aluminum chloride or by reacting a (4-substituted) phenyl-Grignard reagent with a non-haloalkyl nitrile.

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

The invention will now be explained in more detail by way of example.

30 35

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13 150477

Chemical synthesis

Preparation of starting materials

Example 1 4- (2-Naphthalenyloxy) -1- (phenylmethyl) piperidine hydrochloride

To a stirred suspension of 1.80 g (37.5 mmol) of pentane washed 50% sodium hydride dispersion in 50 ml of dry dimethylformamide under argon is added a solution of 4.75 g (25.0 mmol) of 1-phenylmethyl-4 -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 is heated at 75 ° C for 23 hours, cooled, poured into ice water and extracted twice with ether. The extracts are washed with water and brine, dried over magnesium sulfate and filtered. The filtrate is treated with HCl / methanol and the resulting 4- (2-naphthalenyloxy) -1- (phenylmethyl) piperidine hydrochloride is recrystallized from butanone / methanol. Melting point 242-244 ° C.

Example 2 4- (1-Naphthalenyloxy) -1-phenylmethylpiperidine hydrochloride When 1-fluoronaphthalene is used instead of 2-fluoronaphthalene, the title compound is obtained, mp 222-224 ° C.

Example 3 4- (2-Naphthalenyloxy) piperidine hydrochloride

To a stirred solution of 64.6 g (0.204 mol) of 4- (2-naphthalenyloxy) -1-phenylmethylpiperidine in 500 ml of methylene chloride is added 37.0 ml (0.268 mol) of 2,2,2-trichloroethyl chloroformate and approx. 200 mg of potassium carbonate. The mixture is stirred at room temperature for 48 hours and poured into a volume of ether and water. The organic phase is washed with dilute hydrochloric acid and aqueous potassium carbonate, dried over magnesium sulfate and evaporated in vacuo.

35

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14 150477

The resulting 1- (2,2,2-trichloroethoxycarbonyl) -4- (2-napthalenyloxy) piperidine is dissolved in a mixture of 250 ml of acetic acid, 250 ml of tetrahydrofuran and 125 ml of water. 28.5 g (0.436 mole) of zinc dust is added in portions with stirring and the exothermic reaction is allowed to proceed for 2 1/2 hours. The mixture is filtered and the solvents removed in vacuo. 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 extracted into ether and toluene, and the organic solution is washed, dried over magnesium sulfate and evaporated in vacuo to give 4- (2-naphthalenyl-oxy) piperidine which is redissolved in ethanol / ether. and treated with dry HCl and the hydrochloric acid salt recrystallized from butane / methanol. Melting point 229.5-231.5 ° C.

Example 4 4- (1-Naphthalenyloxy) piperidine hydrochloride When using the method of Example 3, 4- (1-naphthalenyloxy) -1-phenylmethyl) piperidine instead of 4- (2-naphthalenyloxy) -1-phenylmethyl ) piperidine, the title compound is obtained, which is further processed directly in Example 7 below.

The method of the invention

Example 5 4- [4- (2-Naphthalenyloxy) -1-piperidyl] -1-phenyl-1-butanohydrochloride 3 ° A solution of 5.67 g (25 mmol) of 4- (2-naphthalenyl-oxy) ) piperidine, 5.0 g (27.4 mmol) of 4-chloro-1-phenyl-1-butanone, 0.1 g of potassium iodide and 4.5 g of potassium bicarbonate in 100 ml of toluene are heated for 48 hours with stirring on a steam bath. The mixture is partitioned between 100 ml portions of methylene chloride / ether and 35 water and the organic phase is dried, over MgSO4. A dissolve

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An excess of HCl in ether is added and the resulting precipitate is recrystallized from methanol / butanone to give the title compound, m.p. 214-216 ° C.

Example 6 4- [4- (2-Naphthalenyloxy) -1-piperidyl] -1- (4-fluorophenyl) -1-butanone hydrochloride When using the method of Example 5, 4-chloro-1- (4) -fluorophenyl) -1-butanone instead of 4-10-chloro-1-phenyl-1-butanone gives the title compound, mp 219-221.5 ° C.

Example 7 4- [4- (1-Naphthalenyloxy) -1-piperidyl] -1- (4-fluorophenyl) -1-butanone hydrochloride When using the method of Example 5, 4-chloro-1- (4 -fluorophenyl) -1-butanone instead of 4-chloro-1-phenyl-1-butanone and 4- (1-naphthalenyloxy) piperidine hydrochloride instead of 4- (2-naphthalenyloxy) piperidine hydrochloro-20 in the title compound, m.p. 220-222.5 ° C.

Biological Testing The following tests illustrate the antipsychotic activity as well as the potential possibility that the compounds of the general formula I will be able to induce extrapyrimidal side effects.

The tested representative compounds are those prepared according to Examples 6 and 7 of the following formulas;

OCX

0 35 0 / —v 1 h

CH2CH2CH2C "V

4- [4- (2-naphthalenyloxy) -1-piperidyl] -1- (4-fluorophenyl) -1-butanone hydrochloride (prepared according to Example 6), code MDL No. 18.203A, and 5 " 6

CH2CH2CH2C

4- [4- (1-naphthalenyloxy) -1-piperidyl] -1- (4-fluorophenyl) -1- -butanone hydrochloride (prepared according to Example 7), code MDL No. 18.478A.

These compounds are compared to the closely related corresponding phenoxy compound as claimed in the claims of U.S. Patent No. 3,743,645, namely to the general formula set forth therein wherein both R 1 and R 2 are hydrogen and the substituent R at the 1-position of the pyridyl group has meaning 4-benzoylpropyl. It is noted that this compound is not specifically described or identified in U.S. Patent No. 3,743,645. The compound has the structure 9 'o

30 I

0.

CH2CH2CH2C y ~~ F

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4- (4-phenoxy-1-piperidyl) -1- (4-fluorophenyl) -1-butanone hydrochloride, code MDL No. 19.446A.

The following tests are carried out: Sample A:

Antagonism of d-amphetamine-induced lethality in clumped mice

Groups of 16 male mice of the Swiss breed from the laboratory are placed in disposable plastic mouse cages (which have dimensions -10 ne 29 x 18 x 13 cm), which are partially filled with a layer of sawdust.

Wire nets are used to cover the cages so that the animals are confined tightly. They are allowed free access to food and water. During the experiment, room temperature is maintained, ie. as close as possible to 22 ° C.

The animals are treated with the test compound and then treated at selected times with d-amphetamine sulfate at a dose of 9.0 mg / kg administered intraperitoneally and prepared as a solution in distilled water so that a 10 ml / kg administration provides the desired dose. . The number of 20 animals still alive in each group is counted approx. 18 hours after administration of amphetamine.

The dose of test compound that provides protection against amphetamine-induced lethality in 50% of test mice (ED50) is calculated by means of a computer program to analyze quantitative data.

A dose of 9.0 mg / kg of d-amphetamine sulfate administered intraperitoneally corresponds to a result of 80-100% mortality in the control groups. Antipsychotic agents are thought to be specific inhibitors of this effect, exerting an activity at doses far below those which elicit any such clear effects in the mice.

35 o 18 150477

Sample B

Inhibition of Apomorphine Induced Sterotype in Rats Male rats weighing between 100 and 300 g, obtained from the laboratory's available material from colonies of the Sprague-Dawley breed, are housed individually in cages with 1.3 cm galvanized steel wire cloth arranged linearly. with 5 cells of 15 x 15 x 15 cm. Each cell is equipped with a snap door.

All medications and controls consisting of vehicle are injected in doses contained in a standard volume of 10 I / O ml / kg. The standard antagonist apomorphine hydrochloride is prepared as a solution in distilled water containing 0.1% ascorbic acid to inhibit or delay oxidation. The test compound is prepared as a solution or kept as a suspension by means of "tween" 80 in distilled water.

Intraperitoneal injections of the test compounds are made and apomorphine hydrochloride is injected subcutaneously.

The rats are injected at a selected dose of the test compound followed at appropriate intervals of 1.0 mg / kg apomorphine hydrochloride and placed again in their cells. Observed 20 days to determine apomorphine sterotype are initiated 15 minutes after the apomorphine injection and continued for a period of 3 minutes. The observed reactions are recorded and evaluated in terms of the degree and frequency / duration of snuffing, licking and chewing, erection and searching. Uninterrupted, excessive sniffing with the nose pressed through the gap in the wire cage serves to distinguish the behavior from the usually inspired behavior. Chewing and licking are activities that occur without obvious reason or clear motivation. Erection and searching, especially 30 standing upright on the hind limbs with the head bent back and the nose in between the cages in the cage is a behavior not usually observed except occasionally in untreated rats. Rising and reversing without search is an incomplete maneuver, but only rarely observed and therefore not recorded.

150477 o 19

Determination of the mean dose of a selected compound that inhibits the action of apomorphine in half the cases (ED5Q) is obtained by administering graduated doses to various groups of rats, the number of rats showing significant inhibition of apomorphine action being ascertained and recorded. for each group.

EDjj0 is obtained by a computer program based on a Berkson analysis of the dose-effect data. Inhibition of this behavior has previously been thought to be associated with clinical antipsychotic activity; however, it has now been found to more closely reflect the extrapyrimidal propensity of a test compound rather than a favorable antipsychotic effect.

The magnitude of the ratio of the effective dosage of a test compound in the apomorphine antagonism model to the effective dosage in the amphetamine antagonism model is interpreted as a measure of the potential or force of the test compound as antipsychotic agents free of extrapyrimidal side effects. Thus, the difference in behavior obtained by administering known antipsychotic agents is quite consistent with this goal of separating the effects: the well-known neuroleptic haloperidol, which is known to induce a high incidence of extrapyrimidal side effects at antipsychotic doses, thus antagonizes apomorphic agents. 25 fine at low dosage relative to the dose at which the agent is effective in the amphetamine antagonism model, while the well-known neuroleptic thiorhidazine (Mellaril), which exhibits a very low incidence of extrapyrimidal activity at antipsychotic doses, is effective only at the apomorphine antagonism model upon administration. of much higher doses than those which constitute an effective dosage of the amphetamine antagonism model.

The following effective dosages in the amphetamine antagonism and apomorphine antagonism tests and the ratios of the effective dosage in the apomorphine antagonism test 0 20 150477 to the effective dosage in the amphetamine antagonism test and for the acute lethal dose (LD 50) are obtained for the above representative test compounds, MDL 18.203A, MDL 18.478A and MDL 19.466A, respectively, and for the reference compound haloperidol and thiorhidazine, the lethal doses recorded being the dose ranges found to cause death in 50% of the mice administered the test compounds intraperitoneally.

The largest administered dose of the 800 mg / kg MDL 18.478A compound of MDL 18.478A thus proves insufficient to induce death in 50% of the animals tested for acute toxicity and the highest administered doses of both 1- the naphthyloxy compound and 2-naphthyloxy compound MDL 18.203A, i.e. 200 mg / kg and 80 mg / kg are insufficient to counteract the effects of the standard dose of apomorphine in any of the animals tested. Therefore, the ratios that relate these toxic effects to the effective dose of the amphetamine antagonism test are minimum values lower than those obtained by using the true LD ^ q 20 or ED5Q.

The test results mentioned above show that MDL 18.203A and MDL 18.478A, respectively. the naphthyloxy-substituted compounds of this invention, which neuroleptic sedatives are far superior to the corresponding phenoxy-substituted compound defined in the claims of U.S. Patent No. 3,743,645, but are not specifically known herein, compound RMI 19.446A. This superiority is reflected by their greater antipsychotic activity, as demonstrated by an ED5q for the 2-naphthyl-oxy compound of only 0.06 mg / kg and 0.6 mg / kg for the 1-naphthyl-oxy compound in the antiamphetamine test relative to a 1.74 kg / kg for the corresponding phenoxy compound. The superiority of the compounds of this invention is also shown by their lower potential for extrapyrimidal side effects, expressed as absolute as reflected by ED 2Q for the apomorphine antagonist of 22.1 mg / kg for the phenoxy compound as opposed to a dose of 80 mg / kg. of the 2-naphthyloxy compound or 200 mg / kg of the 1-naphthyloxy compound insufficient to inhibit apomorphine-induced stereotype 5 in any of the mice used for the experiment. This reduced potential for extrapyrimidal side effects of the present compounds, expressed relatively, is demonstrated by a ratio of ED 50 for the two samples above 1300 for the 2-naphthyloxy compound and above 330 for the 1-naphthyloxy-10 compound, whereas only 12 , 7 for the phenoxy compound. The superiority of the compounds of this invention is also reflected by their lower toxicity, both expressed absolutely as demonstrated by an LD5Q of 400 to 800 mg / kg for the 2-naphthyloxy compound and greater than 800 mg / kg 15 for the 1-naphthyloxy compound as opposed to a value. of 100-200 mg / kg for the phenoxy compound and as expressed relatively as demonstrated by a ratio of LD 50 to amphetamine ED 2Q of 6700 to 13,000 for the 2-naphthyloxy compound and in excess of 1330 for the 1-naphthyloxy compound in contrast. to a value of only 60 to 120 on the phenoxy compound.

The test results in question are also listed in Table I.

Based on the experiments and tests mentioned above, it is clear that the naphthyloxy compounds of this invention are more active as antipsychotic agents than the prior art phenoxy compounds, while at the same time being far less toxic and likely to produce far inferior or weaker neuromotor side effects than those which have traditionally accompanied the treatment with the conventional antipsychotic agents.

35 22 150477 +) open Φ OOO, 1 -., ¾ Ό oo O cm OIL ^^ HCH oo H cm IGG -H> i 0 \ I ro 1 i IOO Μ X5 oh ooi 5 £ o 'g μ M Oa vo O α3π1Ηβ · Η η rA O -P -P Xi O n

VO Η G G O G G

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Claims (2)

1. Analogous Process for Preparation of 4-- [4- (Naphthalenyloxy) -1-piperidinyl] -1- (phenyl) -1-butanone derivatives of Formula OQ Wherein CH is hydrogen or halogen, or pharmaceutically acceptable acid addition salts thereof, characterized in that a 4- (naphthalenyloxy) piperidine of the formula C acid addition salt thereof, is alkylated with a 4-halo-25-1-phenyl-1-butanone of the formula 0 halo- (CH 2) 3 -C- -¾ VIII wherein halo is chloro, bromo or iodo and R above, in a solvent in the presence of a base and optionally in the presence of a catalytic amount of potassium iodide, and then, if desired, a pharmaceutically acceptable salt thereof is obtained by reaction with a corresponding acid.