GB2061937A - 4-(4-Alkyl-4-aroyl-1-piperidino)- butyrophenones - Google Patents

Abstract

Compounds of the formula <IMAGE> wherein R is hydrogen,alkyl, alkoxy, halogen or trifluoromethyl; R' is hydrogen or halogen; R'' is alkyl; Y is H,OH or oxo; and Z is oxo or a ketal function; and salts thereof. The compounds wherein Y and Z are each oxo can have antipsychotic activity. The compounds can be prepared by reacting novel 4- alkyl-4-aroylpiperidines with 4- halobutyrophenones or by reacting novel protected 4-alkyl-4-cyano- piperidinobutyrophenones with aryl Grignard reagents and subsequent hydrolysis.

Description

SPECIFICATION 4-(4-Alkyl-4-aroyl-1 -piperidino)-butyrophenones This invention relates to 4,4-disubstituted piperidinobutyrophenone derivatives and pharmaceutically acceptable salts thereof which are useful as antipsychotic agents. More particularly, it relates to 4-(4-alkyl-4-aroyl-1-piperidino)-butyrophenones and to intermediates and processes for preparing the same.

Compounds of similar structure but lacking a 4-alkyl substituent on the piperidine ring are known, for example, in U.S. Patents Numbers 3,852,455,3,888,867 and 4,101,662, Netherlands Patent 7,409,752 and Costall et al, Psychopharmacologia, 32(2), 161-170 (1973).

The 4-(4-alkyl-4-aroyl-1-piperidino)-butvrophenones of this invention have the general Formula I

wherein R is hydrogen, alkyl, alkoxy, halogen ortrifluoromethyl; R' is hydrogen or halogen; R" is alkyl; and Y and Z are each an oxygen atom. Pharmaceutically acceptable acid addition salts of the above compounds are also included within the scope of the invention, as are pharmaceutical compositions comprising them and methods for preparing and using them.

The invention further includes compounds having the general Formulae I, II and III

wherein R, R' and R" are as hereinbefore defined; A is CN or CHO; Y is H, OH or an oxygen atom; and Z is a dialkyl ketal or alkylene ketal function, which are key intermediates in the preparation of compounds of Formula I (Y=Z=O).

In the compounds of Formula I, the substituent R is hydrogen, trifluoromethyl, alkyl, especially straight or branched-chain C1 4 alkyl, alkoxy, especially straight or branched-chain C1.4 alkoxy, or a halogen atom such as fluorine, chlorine or bromine. The R substituent may be in the ortho, meta or para position on the phenyl radical.

The substituent R' is a hydrogen atom or a halogen atom such as fluorine, chlorine or bromine, especially fluorine.

The R" substituent is an alkyl group, preferably straight or branched-chain C1.4 alkyl. Especially preferred alkyl groups for alkyl and alkoxy substituents R and R" are methyl, ethyl, propyl and isopropyl.

The substituent Y is an oxygen atom or H, OH. In the latter case, a mixture of stereoisomers is obtained. All enantiomers thereof are within the scope of the invention and may be oxidized to the preferred compounds of Formula I, where Y=Z=O.

The substituent Z is an oxygen atom or a dialkyl or alkylene ketal function, e.g., dialkoxy of 1-8, preferably 1-3 carbon atoms in each alkoxy group, e.g., methoxy or ethoxy, and alkylenedioxy of 2-8, preferably 2-4, carbon atoms, having 2 or3 carbon atoms in the chain between the oxygen atoms, e.g., ethylenedioxy, 1,2-propylenedioxy and trimethylenedioxy.

The preferred compounds of this invention are compounds of Formula I wherein R is hydrogen, p-fluoro, p-chloro, p-methyl, p-methoxy or m-trifuloromethyl; R' is a fluorine atom; R" is methyl; and Y and Z are each an oxygen atom.

The invention also includes the pharmaceutically acceptable acid addition salts of the compounds of the hereinbefore set forth formulae, such as those salts with inorganic acids such as, for example, hydrochloric, hydrobromic, sulphuric, phosphoric acids and the like and with organic carboxylic acids such as, for example, acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic and dihydroxymaleic, benzoic, phenylacetic, 4-aminobenzoic, 4-hydroxybenzoic, anthranilic, cinnamic, salicylic, 4-aminosalicylic, 2-phenoxybenzoic, 2-acetoxybenzoic, mandelic acid and the like.

Illustrative of compounds of this invention are, for example, 4-(4-benzoyl-4-methyl-1 -piperidino)-p fluorobutyrophenone, 4-(4-p4luornbenzoyl-4-methyl-1 -piperidino)-p4luorobutyrophenone, 4-(4-p- chlorobenzoyl-4-methyl-l -piperidino)-p-fluorobutyrophenone, 4-(4-p-methylbenzoyl-4-methyl-l -piperidino)- p4luorobutyrophenone, 4-(4-p-methoxybenzoyl-4-methyl-1 -piperidino)-p-fluorobutyrophenone, and 4-(4-m trifluoromethylbenzoyl-4-methyl-1 -piperidino)-p-fluorobutyrophenone.

The compounds of Formula I (Y=Z=O) and their acid addition salts are potent antipsychotic agents. In addition, they are effective analgesics, as shown by biockade of writhing induced by acetic acid. The preferred species are also anticonvulsants, as shown by prevention of metrazol-induced convulsions. They can be administered in the form of pharmaceutical preparations in unit dosages suitable for oral or parenteral administration. The pharmaceutical preparations are preferably in solid form such as, for example, capsules, pills, or tablets, optionally containing, in addition to the active compounds, a significant quantity of a pharmaceutically acceptable carrier. The compounds may be administered to animals, including birds, rats, mice, dogs, cats, horses, pigs, cows, sheep, warm-blooded animals, mammals, and humans.The quantity of the active compound of Formula I (Y=Z=O) in the unit dosage can vary over a wide range, for example to provide about 0.005-10 mg/kg of body weight of the treated subject per dose to achieve the desired effect. The effect can be obtained, for example, by consumption of from one to three 0.5-25 mg tablets taken 1-4 times daily.

The compounds of this invention can be used in the management of manifestations of psychotic disorders and can thus be used in a manner similar to haloperidol, a known antipsychotic agent. Their potency as antipsychotic agents is reflected by pronounced blocking of amphetamine grouped toxicity using standard test conditions. Additional evidence of the neuroleptic activity of the compounds of the invention is illustrated by their effectiveness in inhibiting pernicious preening in mice, in blocking conditioned avoidance behavior in rats, and apomorphine stereotypy.

The following reaction scheme illustrates one method of preparing compounds according to the invention: Scheme 1t

wherein R, R' and R" are as defined hereinbefore and Xis a reactive halogen such as bromine, chlorine or iodine, or an equivalent reactive leaving group. The alkylation reaction is normally carried out in the presence of an acid acceptor, such as, for example, sodium or potassium carbonate or bicarbonate, and is optionally catalyzed by a small amount of potassium iodide, in a suitable solvent. The reaction is generally effected over the course of about four hours to about three days, advantageously at an elevated temperature such as the boiling point of the solvent.Suitable solvents include aromatic hydrocarbons such as toluene, xylene orchlorobenzene, ketones such as methyl isobutyl ketone, or lower alcohols such as ethanol, propanol, butanol and the like. Preferably, the reaction is run using potassium bicarbonate in toluene at reflux. The cooled reaction mixture is partitioned between an organic and aqueous phase, and the product isolated from the organic phase after removal of solvents. Alternatively, the product may be precipitated from the organic phase as a salt, by adding an organic or mineral acid. Further purification may be effected by chromatography and/or recrystallization.

The novel 4-alkyl-4-aroyl-piperidine intermediates II and salts thereof may be prepared as follows: Scheme 2: Commercially available 4-cyanopyridine is converted to its 1-methylpyridinium salt by reaction with methyl iodide in a solvent such as acetone. The 4-cyano-1-methyl-pyridinium iodide is isolated and reduced with sodium borohydride in aqueous ethanol, to form 4-cyano-1 -methyl-1 ,2,5,6-tetrahydropyridine, which is catalytically hydrogenated to 4-cyano-1 -methylpiperidine.

Alkylation is effected by forming an anion at C4 with an appropriate strong non-nucleophilic base, followed by reaction with an appropriate alkyl halide, in a suitable solvent.

Suitable such non-nucleophilic bases include lithium diethylamide, lithium diisopropylamide, sodium hexamethyldisilazane, potassium hydride sodium amide, and the like. Suitable such alkyl halides include methyl iodide, ethyl bromide or iodide, and the like. Suitable solvents include polar, aprotic solvents such as tetrahydrofuran (THF), dimethoxyethane, hexamethylphosphoramide, and the like. Mixtures of solvents may be used. The reaction is normally effected at -20 to OOC, over 0.5-4 hours. The reaction mixture is quenched with water and the alkylated product extracted with an organic solvent such as benzene, toluene, chloroform-, methylene chloride, and the like, followed by conventional recovery.

The resultant4-cyano-4-alkyl-1-methylpiperidine is then reacted with an appropriate substituted or unsubstituted phenyl Grignard reagent or a substituted or unsubstituted phenyl lithium V. The Grignard reaction is effected in a solvent such as ether, THF, benzene, and the like, or mixtures thereof, THF being preferred. The reactants are refluxed for 2-18 hours, preferably about 8 hours. The cooled reaction is quenched by addition of water. Partition of the product between an organic and an aqueous phase, separation of the organic phase, washing with brine, drying over Na2SO4, and evaporation of the solvent gives the 1-methyl derivative of intermediate II.

Demethylation is effected by reaction with 2,2;2-trichloroethyl chlorocarbonate to form the corresponding trichloroethyl carbamate, followed by reductive cleavage with zinc and acetic acid to form II. The reaction with trichloroethyl chloroformate is effected in the presence of an acid acceptor, typically potassium carbonate, in a suitable solvent such as benzene, toluene, dichloroethane, or mixtures thereof, generally at reflux temperature of the solvent. The crude trichloroethyl carbamate intermediate is isolated from the organic phase after partition, acid, base and brine washes, drying and evaporation of the solvent. Reductive cleavage is effected in acetic acid by portionwise addition of zinc metal (e.g., zinc dust) at room temperature and briefly on the steam bath.Filtration, basification, extraction from the basic aqueous phase, base and brine washing, drying and evaporation of the organic phase result in the isolated 4-benzoyl-4 methylpiperidine intermediate II.

The compounds of Formula IV are commercially available or may be prepared by procedures well-known in the art.

An alternative synthesis of the compounds of the invention is the following scheme: Scheme 3: A ketal of a 4-(4-alkyl-4-cyano-1 -piperidino)-butyrophenone Ill (A=CN) is reacted with a substituted or unsubstituted phenyl Grignard reagent or phenyl lithium, in a solvent such as benzene, toluene, THF, ether, and the like, or mixtures thereof. The reaction mixture is refluxed for 2-18 hours, preferably about 8 hours, quenched with water, and the ketal of a 4-(4-alkyl-4-aroyl-1-piperidino)-butyrophenone is isolated after partition, washing, drying and evaporation of the organic phase.The ketal is hydrolyzed by stirring and warming for about 4 hours in aqueous THF or ethanol containing a mineral acid such as HCI, after which the solution is made alkaline and the product ketone (I, Y=Z=O) is isolated after partition, washing, drying and evaporation of the solvent.

The novel 4-(4-alkyl-4-cyano-1-piperidino)-butyrophenone ketals Ill (A=CN) used in the reaction of Scheme 3 may be prepared as follows: Scheme 4: Commercially available piperidine-4-carboxamide is converted to 4-cyano-piperidine, typically by reaction with trifluoroacetic anhydride, followed by hydrolysis of the resultant 4-cyano-1 -trifluoroacetylpiperidine.

Alkylation with a 4-halobutyrophenone ketal, typically the ethylenedioxy derivative, is effected under conditions analogous to Scheme 1. This is followed by alkylation at C4 of the piperidine ring, through an anion typically formed using lithium diisopropylamide, followed by addition of the appropriate alkyl halide, analogous to Scheme 2, to give intermediate Ill (A=CN).

Preparation of the 4-halobutyrophenone ketals (IV ketals) used in the reaction of Scheme 4, is effected by reacting an appropriate glycol in benzene or toluene with a commercially available 4-halobutyrophenone, catalyzed by p-toluenesuslfonic acid (HOTs) with azeotropic water removal, typically by use of a Dean-Stark trap. Reaction time varies from 12 to 72 hours, generally 40-48 hours.

A further alternative synthesis of the compounds of the invention is a variant of the sequence of Scheme 3 and is the following scheme: Scheme 5: The alkylated cyanopiperidinobutyrophenone ketal, prepared according to Scheme 4, is reduced to an aldehyde with a hindered hydride reducing agent, preferably diisobutylaluminium-hydride (DIBAH). The reduction is effected in a solvent such as benzene, toluene, THF, and the like, or mixtures thereof, at 0-25"C for 1-18 hours, preferably about 6 hours. The intermediate imine salt is quenched with methanol, the solvent removed, and the crude residue taken up in an aqueous organic solvent, preferably THF/H2O.The imine is hydrnlyzed with 1 equivalent of a weak acid such as tartaric acid (0.5 mole tartaric acid per mole of imine), at about 0 C for 1-6 hours, preferably about 2 hours. The resultant aldehydo-ketal III (A=CHO) is isolated by partition from slightly basic solution, washing, drying and evaporation of the organic solvent.

Reaction of the aldehyde with a Grignard reagent or a phenyl lithium, in an ether solvent at 00room temperature, following by quenching with saturated Na2SO4 or water, produces the hydroxyketal I (Y=H(OH), Z=ketal) as an isolable mixture of stereoisomers. Oxidation of the secondary benzylic alcohol to a ketone and hydrolysis of the ketal to a ketone may be done in any order or concurrently. It is convenient to effect the Grignard reaction in THF, quench with a minimum of saturated Na2SO4, oxidize in situe with Jones reagent (CrO3/dil.H2SO4/acetone) or the like, and let stir for about four hours to hydrolyze the ketal. The mixture is made alkaline, the produce diketone I (Y=Z=O) is partitioned, and the organic extracts washed, dried and freed of solvent.Other suitable oxidizing agents include CrO3/HOAc, CrO3/pyridine, pyridinium chlorochromate, manganese dioxide, and the like.

The following examples are illustrative of the invention.

EXAMPLE 7 4p-Fluorobenzoyl-4-methylpiperidine (II, R=p -F, R"=CH3J To a solution of 104 g (1.0 mole) of 4-cyanopyridine (Aldrich Chemical Company), dissolved in 800 ml of acetone, is added 70 ml (1.12 mole) of methyl iodide, and the solution is stirred overnight The resultant mixture is filtered and the crystals are washed with benzene and dried to give 86.6- 9 of 4-cyano-1 methylpyridinium iodide.

The salt is dissolved in 500 ml- water and 100 ml ethanol, and 19 g (0.5mole) of sodium borohydride is added in portions to the stirred, cooled solution. After stirring overnight, the reaction mixture is saturated with salt and sodium hydroxide solution is added, followed by extraction with ether and methylene chloride.

The combined extracts are then washed with sodium hydroxide and saturated salt solution and dried over sodium sulfate. Removal of the solvent and distillation at aspirator pressure gives 36.9 g of 4-cyano-1 methyl-1,2,5,S4etrn hydropyrid i ne, b.p.104-107DC.

Catalytic hydrogenation of 15.0 g of the tetrahydropyridine in 120 ml dioxane using 1.5 g of palladium on charcoal and 1.0g of calcium carbonatefor5hours,followedbyfiltration and concentration produces a residue which after distillation gives 13.0 g of crude 4-cyano-1 -methylpiperidine, b.p. 100-1 060C at aspirator pressure.

To a solution of lithium diisopropylamide, prepared by adding 145 ml of 1.67 M n-butyl lithium in hexane (242 mmoles) to 40 ml of diisopropylamine in 325 ml of dimethoxyethane (DME) at -15"C under an argon atmosphere, is added 20.0 g (161 mmoles) of4-cyano-1-methylpiperidine to form the anion, which is alkylated with 15.5 ml (250 mmoles) of methyl iodide. The reaction mixture is poured into water and extracted with ether. The ether extracts are washed with water, brine, dried (MgSO4), filtered, concentrated in vacuo, dissolved in hexane, filtered and the filtrate concentrated and distilled to give 6.7 g of 4cyano-1 4-dimethylpiperidine, b.p. 103-106"C at aspirator pressure.

Absolution of 6.5 (47 mmoles) of 4-cyano-1,4-dimethylpiperidine in 50 ml of benzene is added dropwise to the Grignard reagent prepared from 5.8 g of magnesium (238 mmoles) and 41.6 g (238 mmoles) of p-bromofiuorobenzene in 200 ml oftetrahydrofuran (THF). Benzene is added while distilling off solvent until the head temperature reaches 76.5or, and the reaction mixture is refluxedfor 22 hours, then treated with a small amount of water and alkali, filtered, and the salts washed with ether. The product is extracted into acid, the acid layer made basic and extracted with ether.The ether extract is washed with brine, dried over magnesium sulfate, and concentrated to give 4.6 g of 1,4-dimethyl-4-p-fluorobenzoylpiperidine A further 4.7 g of the product is obtained by dissolving the magnesium salts in acid, filtration, addition of alkali, ether extraction and concentration of the ether extract.

Demethylation is effected by heating 9.3 g (39.5 mmoles) oftheforegoing N-methylpiperidine derivative with an excess of 2,2,2-trichloroethyl chlorocarbonate in the presence of potassium carbonate in 150 ml of benzene. The initial precipitate is dissolved with 100 ml of 1,2-dichloroethane, and the reaction mixture is refluxed. The cooled mixture is washed with aqueous hydrochloric acid, aqueous sodium carbonate, and brine, dried over sodium sulfate and concentrated to give 16.5 g of the corresponding trichloroethyl carbamate. The latter is dissolved in 85 ml of glaciai acetic acid and treated portionwise with 13 g of zinc dust After stirring at room temperature for about 1 hours, an additional 9 g of zinc dust is added and the reaction mixture heated briefly on a steam bath.The cooled reaction mixture is filtered, and the residue washed with water, methanol and ethanol. The combined filtrates are diluted with water and ice and made basic with sodium hydroxide, extracted with ether, and the extractswashed with base, brine and dried overmagnesium sulfate. Concentration in vacuo gives 4.6 g of the desired 4-p-fluorobenzyl-4methylpiperidine as a yellow oil which crystallizes on standing. The crude product is suitable for use in the aikylation- reaction of Example 2.

EXAMPLE 2 4-(4-p-Ruornbenzoyl-4methyl- 1-piper/dino)-p-fluorobutyrophenone {I Y=Z= 0, R=R' =p -F,R"=CH3J (hydrochloride salt) Amixture-of4.6g (20.8 mmoles) of 4-p-fluorobenzoyl-4-methykl-piperidine and 5.1 g (25.4mmoles) of 4-chloro-p-fluorobutyrophenone in 90 ml oftoluene containing 4 g of potassium bicarbonate and a small amount of potassium iodide is heated at reflux for 3.5 days. The cooled reaction mixture is then partitioned between ether and dilute aqueous bicarbonate, the ether layer is washed with brine, dried over sodium sulfate and concentrated to a dark brown oil. Chromatography on alumina gives 4.8 g of the desired product as an orange oil which is converted to the hydrochloride and recrystallized twice from butanone to give the hydrochloride salt, m.p. 192-195'C.

EXAMPLE 3 4-(4-Cyano-4-methyl- 1-pip er/din o)-p-fluorobutvrophenone ethylene ketal FIJI, A = CN, R' F, PR'=CH3, Z= OCH2CH2O) 4-Cyanopiperidine is prepared by reacting 130 g (1.02 mole) of piperidine-4-carboxamide (Aldrich Chemical Company) and 454 g (2.16 moles) of trifluoroacetic anhydride, and heating at reflux for 19 hours.

Trifluoroacetic anhydride and trifluoroacetic acid are removed in vacuo, and the residual 4-cyano-1 trifluoroacetyl piperidine is added slowly to 345 g (2.5 moles) of potassium carbonate in 650 ml water and 1500 ml methanol. The reaction mixture is heated until most of the methanol boils off, 500 ml of benzene is added and the solution is heated until the vapor reaches a temperature of 85"C. The cooled reaction mixture is saturated with NaCI, extracted with methylene chloride, and the extracts dried over sodium sulfate and concentrated. The residue is dissolved in ether, filtered, concentrated in vacuo and distilled to give 30.2 of 4-cyanopiperidine, b.p. 115-116"e at aspirator pressure.

; A mixture of 1 1.1 4-chloro-p-fluorobutyrophenone (prepared by ketalizing the ketone with ethylene glycol in benzene/HOTs using a Dean-Stark trap) and 21 g (0.152 mole) of potassium carbonate in 200 ml of n-butanol are refluxed for 17 hours. Water is added to the cooled reaction mixture, the aqueous layer saturated with NaCI and the organic layer diluted with ether. The aqueous layer is extracted with benzene and the combined organic layers dried over magnesium sulfate and concentrated to give 31.5 g of the ethylene ketal of 4-(4-cyano-1-piperidino)-p-fiuorobutyrophenone as a pale yellow oil.

Alkylation is effected by preparing a solution of lithium diisopropylamide from 30 ml (212 mmoles) of diisorpopylamine and 88 ml (176 moles) of 2 M ethereal methyl lithium in 350 ml DME at -15 C underan argon atmosphere, adding a filtered solution of 36.8 g (98.5 mmoles) of the foregoing ketal in 90 ml of DME to form the anion followed by addition of 11 ml (176 mmoles) of methyl iodide. After the reaction is complete, water is added, the solvent removed in vacuo and the residue partitioned between water and ether, the aqueous layer being again extracted with ether.The combined ethereal extracts are washed with water and brine, dried over magnesium sulfate and concentrated in vacuo to give a partially methylated material which is resubjected to the reaction conditions to give 31.5 g of the desired product as an oil, which partially crystallizes on standing.

EXAMPLE 4 4-F4-p-Fluorobenzoyl-4-methyl- 1-piperidino)-p-fluorobutyrophenone {I, Y=Z= O, R=R' =p -F,!?' CH3) {hydrochloride salt) A solution of 29.0 g (87 mmoles) of the ethylene ketal of 4-(4-cyano-4-methyl-1-piperidino)-p- fluorobutyrophenone of Example 3 in 100 ml of benzene is added dropwise to a stirred solution of the Grignard reagent prepared from 6.4 g (263 mmoles) of magnesium and 46.0 g (263) of p fluorobromobenzene in 350 ml of THF, with distillation of the THF during the addition and addition of 400 ml of benzene, after which the reaction mixture is refluxed for 21 hours.The usual work-up yields an oil which is dissolved in ethanol, treated with 15% hydrochloric acid and warmed to hydrolyze the ketal and imine to ketones. The cooled solution is freed of the bulk of the solvent, made basic and extracted with ether, the combined ether extracts washed with water and brone, dried over magnesium sulfate and concentrated in a vacuum to give a crude oil which after chromatography is converted to the hydrochloride salt.

Recrystallization of the salt from butanone/methanol gives the desired product, m.p. 192-194"C.

EXAMPLE 5 4-(4-p-Chlorobenzoyl-4-methyl- 1-pip er/din o)-p- fluorobut yrophen one (I, Y=Z=O, R=p - Cl, R'=F, !?'= Cll3) thydrochloride salt) By the procedure described in Example 4, and using the Grignard reagent prepared from p bromochlorobenzene, in ether, the cyano ketone being added in THF and both solvents being displaced by benzene, the desired hydrochloride salt is obtained. Recrystallization from benzene/butanone/methanol gives the pure product as star clusters, m.p. 173-175"C.

EXAMPLE 6 4-/4-p-Methylbenzoyl-4-methyl- I-piperidinol-p-fluorobutyrophenenone (I, Y=Z= O, R=p - F, R"= CH3J (h yd- rochloride salt) By the procedure described in Example 4, using the Grignard reagent formed from magnesium and p-bromotoluene, the desired hydrochloride salt is obtained. Recrystallization from butanone/methanol gives the pure product, m.p. 202.5-205.5"C.

EXAMPLE 7 4-(4-p-Methoxybenzoyl-4-methyl- 7-piperidinol-p-fluorobutyrophenone (I, Y=Z= O, R=p - OCH3, R' p -F, R"=CH3) (hydrochloride salt) By the procedure of Example 4, using the Grignard reagent obtained from magnesium and p bromoanisole, the desired hydrochloride salt is obtained. Recrystallization from butanone/benzene gives the pure product, m.p. 201.5-204.5"C.

EXAMPLE 8 4-64-m-Trifluoromethylbenzoyl-4-methyl- 1-piperidino)-p-fluorobutyrophenone (I, Y=Z= O, R=mCF3, R'=p-F,R"=CH3) (hydrochloride salt) By the procedure described in Example 4, using the Grignard reagent obtained from magnesium and m-bromotrifluoromethylbenzene, the desired hydrochloride salt is obtained. Recrystallization from buta none/benzene gives the pure product, m.p. 157-160.5'c.

EXAMPLE 9 4-(4-Benzoyl-4-methyl- 1-piperidino)-p-fluorobutyrophenone (l Y=Z= O, R=H, R'=p-F,F{'=CH3J (h ydrochlor- idle salty To a solution of 10.0 g (30 mmoles) of the ketal of 4-(4-cyano-4-methyl-1-piperidino).p- fluorobutyrophenone in 100 ml of ether is added 28 ml of 2 M phenyl lithium, the solution is stirred overnight at room temperature, poured into water, extracted with ether, and the ether extracts concentrated in vacuo.

The residue is dissolved in ethanol, water and hydrochloric acid are added and the solution heated on a steam bath, cooled, made basic and extracted with ether. The combined ether extracts are washed with water and brine, dried over magnesium sulfate and concentrated in vacuo to give a crude oil.

Chromatography on alumina and treatment with hydrochloric acid gives the desired hydrochloride salt.

Recrystallization from butane/methanol gives the pure product, m.p. 190-1 920C.

EXAMPLE 10 4-(4-p-Fluorobenzoyl-4-eth yl- 1-p/p er/din o)-p-fluorobutyrophen one (I, Y=Z=O, R=R'=p-F, !?'= C2H5) rhyd- rochloride salt) By the procedure of Example 3, using ethyl iodide instead of methyl iodide for the final alkylation, 4-(4-cyano-4-ethyl-1-piperidino)-p-fluorobutyrophenone ethylene ketal is obtained in high yield as an orange oil (Ill, A=CN, R'=F, R"=C2H5, Z=OCH3CH2O).

Reduction of a solution of the cyano ketal prepared above in toluene with a solution of DIBAH in hexane, under an argon atmosphere is followed by quenching with methanol, partition between ether and aqueous alkali, washing of the ether extracts with water and brine, drying (MgSO4) and concentration in vacuo to give a crude imine. The imine is dissolved in aqueous THF, the solution cooled to 0 C, and one equivalent of DL-tartaric acid is added. Only sufficient water is added to form a clear solution.After stirring at 0 C for about 0.5 hour, and quenching with sodium bicarbonate, the mixture is poured into water, extracted with ether, and the ether extracts washed with brine, dried (MgSO4) and concentrated in vacuo to give the desired aldehyde Ill (A=CHO, R'=F, R"=C2H5, Z=OCH2CH2O), suitable for use in the following step.

The crude aldehyde prepared above is dissolved in a minimum of dry THF and added to a solution of a 50% excess of the Grignard reagent prepared from equimolar amounts of magnesium and pbromofluorobenzene in THF. The reaction mixture is stirred at room temperature for 0.5 hour following the addition, then quenched with a slight excess of cold, saturated sodium sulfate. One equivalent of Jones reagent is added dropwise, with stirring, and stirring is continued for 4 hours at room temperature to hydrolyze the ketal. The solution is made alkaline, saturated with NaCI, and extracted with ether, the combined ether extracts washed with water and brine, dried (MgSO4), and concentrated in vacuo to give a crude product which, after chromotography, is converted to the hydrochloride salt.

EXAMPLE 11 Tablet formulation Exemplary of a representative tablet formulation of an active compound of this invention, there may be mentioned the following: PerTablet (a) 4-(4-p-fluorobenzoyl-4-methyl-1 piperidino)-p-fluorobutyrophenone 25.0 mg (b) Wheat starch 3.5mug (c) Lactose 10.0 mg (d) Magnesium stearate 0.5 A granulation obtained upon mixing lactose with a portion of the starch and granulated starch paste made from the remainder of the starch is dried, screened, and mixed with the active ingredient (a) and the magnesium stearate. The mixture is compressed into tablets weighing 39.0 mg each.

Claims (22)

1. Acompound having the formula

wherein R" is CiA alkyl; A is CN, CHO or a group having the formula

wherein R is hydrogen, C14 alkyl, C1 4 alkoxy, fluorine, chlorine, bromine ortrifluoromethyl and Y is H, OH or an oxygen atom; and B is hydrogen or a group having the formula

wherein R' is hydrogen, fluorine, chlorine or bromine and Z' is an oxygen atom or a ketal function selected from dialkoxy of 1-8 carbon atoms in each alkoxy group and alkylenedioxy of 2-8 carbon atoms and 2-3 carbon atoms in the chain between the oxygen atoms; with the proviso that when A is CN or CHO, B is other than hydrogen; or a pharmaceutically acceptable acid addition salt thereof when A is other than CN or CHO, B is other than hydrogen and Y and Z are each an oxygen atom.

2. Acompound oftheformula

wherein R, R' and Z' are as defined in claim 1, or a pharmaceutically acceptable addition salt thereof when Z' is oxygen.

3. A compound as claimed in claim 2 wherein Z' is oxygen, or a pharmaceutically acceptable acid addition salt thereof.

4. A compound as claimed in claim 3 wherein R" is methyl.

5. A compound as claimed in claim 3 or claim 4 wherein R' is fluorine.

6. 4-(4-Benzoyl-4-methyl-1-piperidino)-p-fluorobutyrophenone or a pharmaceutically acceptable acid addition salt thereof.

7. 4-(4-p-Fluorobenzoyl-4-methyl-1-piperidino)-p-fluorobutyrophenone or a pharmaceutically acceptable acid addition salt thereof.

8. 4-(4-p-Chlorobenzoyl-4-methyl-1 -piperidino)-p4luorobutyrophenone or a pharmaceutically acceptable acid addition salt thereof.

9. 4-(4-p-Methylbenzoyul-4-methyl-1 -piperidino)-p4luorobutyrophenone or a pharmaceutically accept able acid addition salt thereof.

10. 4-(4-p-Methoxybenzoyl-4-methyl-1 -piperidino)-p4luorobutyrophenone or a pharmaceutically accept able acid addition salt thereof.

11. 4-(4-m-Trifluoromethyl-benzoyl-4-methyl-1 -piperidino)-p-fluorobutyrophenone or a pharmaceutical ly acceptable acid addition salt thereof.

12. A compound as claimed in claim 1 wherein A is cyano and B is an optionally ketalised aroylalkyl group as defined therein.

13. A compound as claimed in claim 1 wherein B is hydrogen and A is an optionally substituted benzoyi group as defined therein.

14. A compound as claimed in claim 1 wherein A is CHO and B is an optionally ketalised aroylalkyl group as defined therein.

15. A compound as claimed in claim 1 wherein A is an optionally substituted a-hydroxybenzyl group as defined therein and B is a optionally ketalised aroylalkyl group as defined therein.

16. A compound as claimed in claim 3 substantially as herein described.

17. A pharmaceutical composition comprising a compound as claimed in any of claims 3 to 11 and 16 in association with a pharmaceutically acceptable carrier.

18. A composition according to claim 17 in unit dosage form and comprising from 0.5 to 25 mg of the compound per unit dosage.

19. A composition according to claim 17 substantially as described in Example 11.

20. A process for preparing a compound as claimed in claim 3, which comprises reacting a compound as claimed in claim 13 with a compound oftheformula

wherein R' is as defined in claim 1 and Xis a reactive halogen, in the presence of an acid acceptor.

21. A process for preparing a compound as claimed in claim 2, which comprises alkylating 4-cyanopiperidine with a compound of the formula

wherein R' is as defined in claim 1 and Z is a ketal function as defined in claim 1 and Xis a reactive halogen; alkylating the resultant cyanoketal with a C1 < alkyl halide, in the presence of a strong base, to produce a compound as claimed in claim 12; reacting the product with a compound ofthe formula

wherein R is as defined in claim 1 and M is Li or Mg Hai in which Hal is CI, Br or I; and, if desired, hydrolyzing the resultant ketal-ketone in the presence of acid.

22. A process for preparing a compound as claimed in claim 2, which comprises reducing a compound as claimed in claim 12 with a hindered hydride reagent to produce a compound as claimed in claim 14; reacting the productwith a compound of the formula

wherein R is as defined in claim 1 and M is as defined in claim 21, to produce a compound as claimed in claim 15; oxidising the product and, if desired, hydrolysing the ketal.