NL8005890A - 4.4 DIPSTITUTED PIPERIDINOBUTYROPHENONES AND THEIR SALTS. - Google Patents

Description

4,4-disubstituted piperidinobutyrophenones and salts thereof.

This invention relates to 4- (4-alkyl-4-aroyl-piperidino) butyrophenones of general formula 1 as well as their salts with pharmaceutically acceptable acids, which compounds are useful as anti-psychotic drugs.

Compounds of a similar structure but without a 4-alkyl substituent on the piperidine ring are known from US patents 3,852,455, 3,888,867 and 4,101,662, from Netherlands patent application 74.09752 and from an article by Costall et al. in Psychopharmacologia 32 (1973) 161-170. The invention relates to 4- (4-alkyl-4-aroylpiperidino) butyrophenones of the general formula 1, wherein R is hydrogen, alkyl, alkoxy, halogen or trifluoromethyl, R 'is hydrogen or halogen, R "is alkyl and Y and Z are both an oxygen atom and its salts with pharmaceutically acceptable acids The invention also relates to pharmaceutical preparations containing these compounds, and methods for the preparation of the compounds and for the preparation of those preparations.

Furthermore, this invention relates to compounds of general formulas 2 and 3, wherein R, R 'and R "have the previously given definitions, A is cyano or formyl, Y is the combination of H and OH or an oxygen atom and Z is a dialkyl or alkylene ketal, which are key substances in the preparation of compounds of formula 1.

In the compounds of formula 1, the substituent R is hydrogen, trifluoromethyl, alkyl (especially straight or branched chain alkyl of 1-4 carbon atoms), alkoxy (especially of 1-4 carbon atoms) or halogen (fluorine, chlorine or bromine). This substituent can be in the ortho, meta and para position of the phenyl core 80 0589 0 2.

The substituent R "is an alkyl group, preferably branched or unbranched with 1 to 4 carbon atoms. Particular preference is given to methyl, ethyl, propyl and isopropyl.

The substituent Y is an oxygen atom or the combination of H and OH. In the latter case, there is a mixture of stereoisomers. All enantiomers are within the scope of the invention; they can be oxidized to the preferred compounds of formula 1 wherein Y = Z = 0.

The substituent Z is an oxygen atom or a dialkyl or alkylene ketal, ie dialkoxy with 1-8 and preferably 1-3 carbon atoms in any alkoxy group (eg methoxy or ethoxy) or alkylenedioxy with 2-8, preferably 2 -4 carbon atoms (e.g. ethylenedioxy, propylenedioxy-1,2 and -1,3).

The preferred compounds of this invention are those of formula 1 wherein R is hydrogen, p-fluoro, p-chloro, p-methyl, p-methoxy or m-trifluoromethyl, R 'is fluoro and R "methyl and wherein Y and Z both represent an oxygen atom.

The invention also relates to salts of these compounds with pharmaceutically acceptable acids, for example with hydrochloric, hydrobromic, sulfuric, phosphoric, etc., and with organic acids such as acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, fumaric, tartaric, citric acid, ascorbic acid, maleine, hydroxy- and dihydroxy-maleic acid, benzoic acid, phenylacetic acid, 4-aminobenzoic acid, 4-hydroxybenzoic acid, anthranilic acid, cinnamic acid, salicylic acid, 4-amino-salicylic acid, 2-phenoxybenoic acid, 2-acetoxybenzoic acid , d.

Examples of compounds according to the invention are 4- (4-benzoyl-4-methylpiperidino) -p-fluorobutyrophenone, 4- (4-p-fluorobenzoyl-4-methylpiperidino) -p-fluorobutyrophenone, 4- (4-p -chlorobenzoyl-4-methylpiperidino) -p-fluorobutyrophenone, 4- (4-p-methylbenzoyl-4-methylpiperidino) -p-fluorobutyrophenone, 4- (4-p-methoxybenzoyl-4-methylpiperidino) -p-fluorobutyrophenone and 4 - (4-m-trifluoromethylbenzoyl-4-methylpiperidino) -p-fluorobutyrophenon, 80 0583 0 * i 3

The compounds of formula 1 (Y = Z = 0) and their salts are strong agents against psychosis. In addition, they are effective analgesics, which shows that they eliminate the distortion caused by acetic acid. The preferred fabrics also work against convulsions, especially those caused by metrazole. They can be administered orally and parenterally in the form of pharmaceutical preparations. These are preferably solid preparations, such as capsules, pills and tablets, which optionally contain an important amount of pharmaceutically acceptable carrier in addition to the active substances.

The substances can be administered to animals, including birds, rats, mice, dogs, cats, horses, pigs, cows, sheep, warm-blooded animals, mammals and humans.

The amount of active compound of compound 1 may vary over a wide range in the unit dose, enough to provide 0.005 to 10 mg per kg of animals to be treated, depending on the desired effect. The effect can be achieved, for example, by taking 1 to 3 tablets with 0.5 to 25 mg of active substance 1 to 4 times a day.

The compounds according to the invention can be used in the treatment of mental disorders, so just like the known haloperidol. Their efficacy as an anti-psychotic agent is evidenced by the marked blocking of amphetamine toxicity under standard test conditions. In addition, their neuroleptic activity is evidenced by the effectiveness in inhibiting the life-threatening appearance of mice, blocking the conditioned avoidance behavior in rats and by an apomorphine stereotype.

A possible method of preparation for the compounds of the invention is to react a compound of formula 2 with a compound of formula 4, wherein R, R 'and R "have the meanings given previously and X represents a reactive halogen or a corresponding reactive leaving group The alkylation is usually carried out in the presence of an acid scavenger such as sodium or potassium carbonate or bicarbonate, and is best catalyzed by a small amount of potassium iodide 80 0 5 8 9 0 4 in a suitable solvent. reaction usually lasts from 4 hours to 3 days, best at elevated temperature such as the boiling point of the solution Suitable solvents are aromatic hydrocarbons such as toluene, xylene and chlorobenzene, 5 ketones such as butanone and lower alcohols such as ethanol, propanol and butanol. The reaction is best with potassium bicarbonate in boiling toluene The cooled reaction mixture is divided between an organic he and an aqueous phase and the product is isolated from organic phase after all solvent has been removed therefrom.

The product can also be precipitated from the organic phase as salt. A further purification can be effected by chromatography and / or recrystallization.

The new 4-alkyl-4-aroylpiperidines according to formula 2 can be prepared as follows: 4-cyano-pyridine from the market is methylated in acetone with methyl iodide, the resulting 4-cyano-1-methylpyridinium iodide is isolated in aqueous NaBH 4 ethanol reduced to 4-cyano-1-methyl-1,2,5,6-tetrahydropyridine which is catalytically hydrogenated to 4-cyano-1-methylpiperidine.

This material is alkylated by treatment with an appropriate alkyl nucleophilic base followed by reaction in a suitable solvent with the appropriate alkyl halide. Suitable non-nucleophilic bases are lithium diethylamide, lithium diisopropylamide, sodium hexamethyldisalazane, potassium hydride and sodium amide. Suitable alkyl halides are methyl iodide, ethyl bromide and iodide, etc. Suitable solvents are the polar aprotic liquids such as tetrahydrofuran, dimethoxyethane, hexamethylphosphoramide, etc. It is also possible to use mixtures of solvents. The reaction normally takes place between -20 ° and 0 ° C and is in a 1 hours to 4 hours completed. The reaction mixture is then poured into water and the alkylation product is separated with an organic solvent such as benzene, toluene, chloroform, methylene chloride and the like, followed by work-up in the usual manner.

The 4-cyano-4-alkyl-methyl-1-piperidine thus obtained is then reacted with a substituted or unsubstituted phenylmagnesium bromide (Grignard reagent). This reaction takes place 8005890% in a solvent such as ether, tetrahydrofuran, benzene, etc., or mixtures thereof, preferably for tetrahydrofuran. Cook for 2 to 18 hours, preferably 8 hours. After cooling, the reaction mixture is poured into water and the product is divided between an organic and an aqueous phase. The organic phase is separated, washed with brine, dried over Na 2 SO 4 and evaporated to dryness. This gives a compound of formula 5.

Demethylation is effected by reaction with 2,2,2-trichloroethyl chloroformate to split methyl chloride off-10 to give a trichloroethyl carbamate; the latter is subjected to reductive cleavage with zinc and acetic acid. The reaction with trichlorethyl chloroformate takes place in the presence of an acid scavenger such as potassium carbonate in a suitable solvent such as benzene, toluene, dichloroethane or a mixture thereof, usually at the boiling point of the mixture. The crude trichlorethyl carbamate is recovered from the organic phase by separating the phases, washing with acid, base and brine, drying and evaporating to dryness. The reductive cleavage is done in acetic acid by adding bits of zinc (generally zinc-20 powder) at room temperature, followed by a short treatment on the steam bath. Filtration, alkalinization, and extraction of the aqueous phase, washing with base and with brine, drying and evaporation finally gives the substituted or unsubstituted 4-benzoyl-4-alkyl-piperidine of formula 2.

The compounds of formula 4 are commercially available or can be prepared in ways known in the art.

Another possible method of preparation of the compounds of the invention is the following: A compound of formula 3, wherein R. and R "have the meanings given previously, A is cyano and Z represents a ketal group, is reacted with an unsubstituted or substituted phenyl lithium or magnesium bromide to give a compound of formula 1 wherein Z is a ketal group Which is hydrolysed in a known manner In the reaction with the phenyl lithium or magnesium bromide, a solvent 8005890 6 such as benzene, toluene, tetrahydrofuran, ether, or a mixture thereof, is used, and after boiling for 2 to 18 hours (preferably about 8 hours) the reaction mixture is poured into water After separating the organic phase, washing, drying and evaporation, the desired ketal according to formula 1 is obtained. The hydrolysis is carried out by heating for 4 hours with stirring in water / tetrahydrofuran or water / ethanol. which contains a little mineral acid, after which the mixture is made alkaline and the ketone according to formula 1 is separated off in a known manner.

The new 4- (4-alkyl-4-cyano-piperidino) butyro-10-phenone-ketals of formula 3 (A = CN) can be obtained as follows: Commercial 4-carbamoylpiperidine is converted to 4-cyano-piperidine, generally by treatment with trifluoroacetic anhydride followed by hydrolysis of the 4-cyano-15-trifluoroacetylpiperidine. Alkylation with a 4-halobutyrophenone ketal, generally the ethylenedioxy derivative, is carried out under the conditions previously indicated. Then there is an alkylation at C4 of the piperidine ring, as already described for the 4-alkyl-4-cyano-1-methylpiperidine, by first forming an anion with a base such as lithium diisopropylamide and then leaving it with the appropriate alkyl halide comment.

The 4-halobutrophenone ketal required for this is obtained by reacting the commercially available 4-halobutyrophenone in benzene or toluene with the appropriate glycol, under catalysis by p-toluenesulfonic acid and removing water, often with the aid of azetrope. of a water trap according to Dean and Stark. The reaction lasts 12 to 72 hours, usually 40-48 hours.

Another possible preparation method of the compounds according to the invention consists in a reduction of a compound of formula 3 in which R 'and R "have the meanings given earlier, A is cyano and Z represents a ketal group, with a sterically hindered reducing agent such as diisobutylaluminum hydride (DIBAH) to a corresponding compound of formula 3 wherein A is formyl This is then reacted with a substituted or unsubstituted phenyl lithium or magnesium bromide to give a compound of formula 1 wherein Y is the combination of 80 0 5 8 9 0 7 -SJ, H and OH Finally, the secondary hydroxy group is converted to ketone groups by oxidation and the ketal group by hydrolysis.

The reduction is done in a solvent such as benzene, toluene or tetrahydrofuran at 0 to 25 ° C and lasts 1 to 5 18 hours, usually about 6 hours. The reaction mixture is poured into methanol, and after removing the solvents, the residue is taken up in a combination of water and organic solvent (preferably tetrahydrofuran) and the resulting imine with one equivalent of weak acid (1 mol of tartaric acid per mol of imine). 10 is hydrolyzed, which takes 1 to 6 hours, usually about 2 hours, at 0 ° C. The aldehyde obtained is isolated by extraction from weakly basic solution, washing, drying and evaporating to dryness,

The reaction of the aldehyde with the reagent of Grignard or the phenyl lithium is carried out in ether at a temperature between 0 ° and 15 ° C, after which the reaction mixture is poured into water or saturated Na 2 SO 4 solution. This gives the hydroxyketal of formula 1 as an isolatable mixture of stereoisomers.

The oxidation of the secondary alcohol group and the hydrolysis of the ketal group can take place sequentially or simultaneously; the easiest is a reaction with a Grignard reagent in tetrahydrofuran, pouring into the minimum amount of saturated Na 2 SO 2 solution, oxidation in situ with Jones's reagent (CrO 2 / dilute SO 2 / acetone) and still Stir for 4 hours to hydrolyze the ketal. The mixture is then made alkaline and the ketone extracted, the extract washed, dried and evaporated.

Other suitable oxidizing agents are CrO4 in glacial acetic acid or pyridine, pyridinium chlorochromate, manganese dioxide and the like.

The invention is now further illustrated by the following examples.

Example I

4-p-fluorobenzyl-4-methylpiperidine (Formula 2, R = p-F, R "= CH ^)

To a solution of 104 g (1.0 gmol) of 4-cyano-pyridine (Aldrich Chemical Company) in 800 ml of acetone was added 70 ml (1.12 gmol) of methyl iodide. After stirring overnight, the mixture was filtered and the crystals were washed with benzene and dried. This gave 86.6 g of 4-cyano-1-methylpyridinium iodide,

Rn n r 89 0 8

To a solution of this salt in 500 ml of water and 100 ml of ethanol was added 19 g (0.50 gmole) of sodium borohydride under cooling and stirring. After stirring overnight, the reaction mixture was saturated with salt and NaOH was added and extracted with ether and methylene chloride. The extracts were washed together with NaOH and saturated brine, dried to dryness and evaporated to dryness on the water jet pump. This gave 36.9 g of 4-cyano-1-methyl-1,2,5,6-tetrahydropyridine, bp. 104-107 ° C.

Catalytic hydrogenation of 15 g of this tetrahydropyridine in 120 ml of dioxane with 1.5 g of palladium-on-charcoal and 1.0 g of calcium carbonate gave after 5 hours reaction, filtration and evaporation to dryness a residue containing 13.0 g of crude 4- cyano-1-methylpiperidine, bp. 100-106 ° C at water jet pump pressure.

To a solution of lithium diisopropylamide, obtained by adding 145 ml of 1.67 M n-butyl lithium in hexane (242 mg mol) under argon at -15 ° C to 40 ml of diisopropylamine in 325 ml of diethoxyethane, was added 20.0 g (161 mgmol) 4-cyano-1-methylpiperidine, then 15.5 ml (250 mgmol) methyl iodide. The reaction mixture was poured into water and extracted with ether. The extracts were washed with water and brine, dried over MgSO4, filtered, and evaporated in vacuo. The residue was taken up in hexane, this solution was filtered and the filtrate evaporated to dryness. The latter residue was distilled to give 6.7 g of 4-cyano-1,4-dimethylpiperidine, bp.

25 103-106 ° C at water jet pump pressure.

A solution of 6.5 g (47 mg mol) 4-cyano-1,4-dimethylpiperidine in 50 ml benzene was added dropwise to the Grignard reagent from 5.8 g (238 mg mol) magnesium and 41.6 g (238 mg mol ) p-bromofluorobenzene in 200 ml of tetrahydrofuran. Benzene was added with distillation of the solvent until the distillation temperature reached 76.5 ° C, after which the reaction mixture was refluxed for 22 hours. A little water and alkali were then added, filtered and the salts washed with ether. The product was extracted from the ether solution with acid, and this acid phase was made basic and extracted again with ether. This ether extract was washed with brine, dried on MgSO4 80 and evaporated to dryness. This gave 4.6 g of 1,4-dimethyl-4-p-fluorobenzoylpiperidine. A further 4.7 g of product was obtained by dissolving the magnesium salts in acid, filtering, adding alkali, re-extracting with ether and evaporating the ether extract to dryness.

Demethylation was achieved by treating 9.3 g (39.5 mg mol) of this N-methylpiperidine derivative in 150 ml of benzene in the presence of excess 2,2,2-trichloroethyl chloroformate. The initial precipitate was dissolved in 100 ml of 1,2-dichloroethane and the reaction mixture was refluxed. After cooling, the reaction mixture was washed with dilute hydrochloric acid, dilute NagCO 2 and brine, dried over Na 2 SO 4 and evaporated to give 16.5 g of the corresponding trichloroethyl carbamate. The latter was dissolved in 85 ml of glacial acetic acid, to which 13 g of zinc powder was added in bits. After stirring at room temperature for about 105 minutes, another 9 g of zinc powder was added and the reaction mixture was briefly heated on a steam bath. After cooling, the reaction mixture was filtered and the residue washed with water, methanol and ethanol. The filtrates were diluted with water and ice, basified with NaOH, and extracted with ether. The extracts were washed with base and brine and dried over MgSO4. Evaporation to dryness under vacuum gave 4.6 g of the desired 4-p-fluorobenzoyl-4-methylpiperidine as a yellow oil which crystallized on standing. The crude product was readily useful for the alkylation of Example II.

Example II

4- (4-p-fluorobenzoyl-4-methylpiperidino) -p-fluorobutyrophenone (Formula 1, Y = Z = 0, R = R '= pF, R "= CH 2; as hydrochloride) 30 A mixture of 4.6 g (20.8 mgmol) 4-p-fluoro-benzoyl-4-methylpiperidine and 5.1 g (25.4 mgmol) 4-chloro-p-fluorobutyrophenone in 90 ml toluene containing 4 g KHCO4 and a little KJ was refluxed for 3 days After cooling, the reaction mixture was partitioned between ether and dilute aqueous bicarbonate, the ether layer was washed with brine,

After drying SO 2 and evaporating to a dark brown oil, chromatography over Algaf 4.8 g of the desired product as orange oil which was converted into the hydrochloride and recrystallized twice from butanone; mp. 192-195 ° C.

Example III

4- (4-cyano-4-methylpiperidino) -p-fluorobutyrophenone-ethylene ketal (Formula 3, A = CN, R "- F, R" = CEi, Z = 0CH 2 CH 2 O).

First, 4-cyano-piperidine was prepared by reacting 130 g (1.02 gmole) of 4-carbamoylpiperidine (Aldrich Chemical Company) with 454 g (2.16 gmole) of trifluoroacetic anhydride, After refluxing for 19 hours, the trifluoroacetic acid and excess anhydride was removed in vacuo and the remaining 4-cyano-1-trifluoroacetylpiperidine was slowly added to 345 g (2.5 gmole) of CO 2 in 650 ml of water and 1500 ml of methanol.

This mixture was heated until most of the methanol had boiled away.

Now 500 ml of benzene was added and the solution was added until the vapor had a temperature of 85 ° C. After cooling, the reaction mixture was saturated with NaCl, extracted with methylene chloride,

The extracts were dried over Na2SO4 and evaporated to dryness. The residue was taken up in ether, filtered, evaporated in vacuo and distilled. This gave 30.2 g of 4-cyanopiperidine, bp. 115—116 ° C at water jet pump pressure.

A mixture of 11.1 g (0.10 gmole) of 4-cyanoperidine, 24.8 g (0.10 gmole) of ethylene ketal of 4-chloro-p-fluoro-butyrophenone (obtained by the ketone with ethanediol in benzene with 25 to ketalize some p-toluenesulfonic acid and collect the resulting water according to Dean and Stark) and 21 g (0.152 gmol) K 2 CO 2 in 200 ml n-butanol was refluxed for 17 hours.

After cooling, water was added, the aqueous layer saturated with NaCl, and the organic layer diluted with ether. The aqueous layer was extracted again with benzene and the extracts were dried together over MgSO4 and evaporated to dryness. This gave 31.5 g of ethylene ketal of 4- (4-cyano-piperidino) -p-fluorobutyrophenone as pale yellow oil. To a mixture of 88 ml 2M (176 mgmol) methyl lithium in ether and 350 ml dimethoxyethane was added at -15 ° C under argon 30 ml (212 mgmol) 35 diisopropylamine. To this was added a filtered solution of 36.8 g (98.5 mgmol) of the above-mentioned ketal in 8005890 31 90 ml of dimethoxyethane, then 11 ml (176 mgmol) of methyl iodide. After the reaction was completed, water was added, the solvent removed in vacuo, and the residue partitioned between water and ether. The water layer was again extracted with ether. The ether extracts were washed together with water and brine, dried over MgSO 4, and evaporated to dryness under vacuum. The material thus obtained was partially methylated and again subjected to the same reaction. This gave 31.5 g of the desired product as an oil which crystallized on standing.

Example IV

4- (4-p-fluorobenzoyl-4-methylpiperidino) -p-fluorobutyrophenone (Formula 1, Y = Z = 0, R = R "= p-F, R" = CH 2 J as hydrochloride).

A solution of 29.0 g (87 mgmol) of ethylene ketal of 4- (4-cyano-4-methylpiperidino) -p-fluorobutyrophenone according to Example III in 300 ml of benzene was added dropwise to a stirred solution of the Grignard reagent from 6.4 g (263 mgmol) of magnesium and 46.0 g (263 mgmol) of p-fluorobromobenzene in 350 ml of tetrahydrofuran. While 400 ml of benzene was gradually added, the THF was distilled off, and then the mixture was refluxed for 21 hours.

A usual work-up gave an oil which was dissolved in ethanol and heated with 35% hydrochloric acid to hydrolyze the ketal and imine to ketones.

After cooling, the reaction mixture was stripped of most of the solvent, made basic, and extracted with ether,

The ether extracts were washed together with water and brine, dried over MgSO4, and concentrated in vacuo to an oil which was converted to the hydrochloride after chromatography. Recrystallization of the salt from butanone / methanol gave the desired product, mp. 392-194 ° C.

8005890 12

Example V

4- (4-p-chlorobenzoyl-4-methylpiperidino) -p-fluorobutyrophenone (Formula 1, Y = Z = 0, R = p-Cl, R '= F, Rn = CH 2; as hydrochloride) According to Example IV and using the Grignard reagent from p-bromochlorobenzene in ether, adding the cyanone ketone in tetrahydrofuran and replacing both solvents with benzene, the above hydrochloride was obtained. Recrystallization from benzene / butanone / methanol gave a pure product as star-shaped aggregates; mp. 173-175 ° C.

Example VI

4- (4-p-Tnethylbenzoyl-4-methylpiperidino) -p-fluorobutyrophenone (Formula 1, Y = Z = 0, R => p-CH ^, R '= pF, R "= CH ^; as hydro-15 chloride)

In accordance with Example IV, using the Grignard reagent from magnesium and p-bromotoluene, the above compound was obtained. Recrystallization from butanone / methanol gave the pure product; mp. 202 £ -205 | C.

Example VII

4- (4-p-methoxybenzoyl-4-methylpiperidino) -p-fluorobutyrophenone (Formula 1, Y = Z = O, R = p-OCH 2, R '* p-F, R "= CH 2 J as hydrochloride).

In accordance with Example IV, using the Grignard reagent from magnesium and p-bromoanisole, the above-mentioned compound was obtained. Recrystallization from butanone / benzene gave the pure product; mp. 201f-204 £ ° C. Example VIII

4- (4-m-trifluoromethylbenzoyl-4-methylpiperidino) -p-fluorobutyro-30-phenone (Formula 1, Y = Z = 0, R * m-CF ^, R '= pF, R "= CH ^; as hydrochloride ).

In accordance with Example IV, using the Grignard reagent from magnesium and m-bromotrifluoromethyl-35 benzene, the above salt was obtained. Recrystallization from butanone / benzene gave the pure product; mp. 157-160 ° C.

80 0589 0 13

Example IX

4- (4-Benzoyl-4-methylpiperidino) -p-fluorobutyrophenone (Formula 1, Y = Z = 0, R = H, R "= p-F, R" - CH 3; as hydrochloride).

To a solution of 10.0 g (30 mgmol) ketal of 4- (4-eyane-4-methylpiperidino) -p-fluorobutyrophenone in 100 ml ether, 28 ml 2M phenyllithium was added. After stirring overnight at room temperature, the reaction mixture was poured into water.

This was extracted with ether and the ether extracts evaporated to dryness together under vacuum. The residue was taken up in ethanol, water and hydrochloric acid were added, and the solution was heated on a steam bath. After cooling, it was made basic and extracted with ether. The ether extracts were washed together with water and brine, dried over MgSO 4, and concentrated in vacuo to a crude oil. Chromatography on Alen treatment with HCl gave the desired hydrochloride. Recrystallization from butanone / methanol gave the pure product; mp, 190-192 ° C.

Example X.

4- (4-p-fluorobenzoyl-4-ethylpiperidino) -p-fluorobutyrophenone 20 (Formula 1, Y = Z = 0, R = R '= p-F, R ”= * C ^ H ^; as hydrochloride)

According to Example III, but with ethyl iodide instead of methyl iodide in the last alkylation, the 4- (4-cyano-4-ethylpiperidino) -p-fluorobutyrophenone-ethylene ketal was obtained in high yield as orange oil (Formula 3, A = CN , R '»25 F, R" = C2H5, Z = 0CH2CH20),

A solution of this cyanide in toluene was reduced under argon with a solution of DIBAH in hexane. The reaction mixture was poured into methanol and partitioned between ether and dilute alkali. The ether extraction was washed with water and brine, dried over MgSO4 and concentrated in vacuo. The crude imine thus obtained was dissolved in a mixture of water and tetrahydrofuran, and after cooling to 0 ° C, an equivalent DL-tartaric acid was added thereto. No more water was added than necessary to obtain a clear solution. After stirring at 0 ° C for one hour and tapping with NaHCO4, the reaction mixture was poured into water and extracted with ether.

8005890 14

The ether extracts were washed with brine, dried over MgSO 4 and evaporated in vacuo to give the desired aldehyde of formula 3 (A = CHO, R '= F, R "= C 2 O 2 CH 2 CH 2 O). This was immediate usable for the next step.

The crude aldehyde thus obtained was dissolved in the minimum amount of dry tetrahydrofuran and added to a solution of a 50% excess of Grignard reagent from equimolecular amounts of magnesium and p-bromofluorobenzene in tetrahydrofuran. After a further 1 hour stirring at room temperature, a small excess of cold, saturated Na 2 SO 2 solution was added. Then, one equivalent of Jones reagent was added dropwise with stirring. Stirring was then continued at room temperature for 4 hours to hydrolyze the ketal. The solution was then made alkaline, saturated with NaCl, and extracted with ether.

The ether extracts were washed together with water and brine, dried over MgSO4, and evaporated to dryness under vacuum. This gave a crude product which was converted to the hydrochloride after chromatography. Example XI Tablets.

An example of a representative formulation of an active substance according to this invention as tablets has the following composition: per tablet (a) 4- (4-p-fluorobenzoyl-4-methyl-piperidino) -p-fluorobutyrophenone 25 .0 mg (b) Wheat starch 3.5 mg (c) Laetose 10.0 mg (d) Magnesium tearate 0.5 mg 30 A starch granulate was made from part of the starch. This was mixed with the rest of the starch and the lactose, then the active (a) and the magnesium stearate were added. The mixture was compressed into 39.0 mg tablets each.

35 80 0589 0

Claims (18)

A compound of formula 6, wherein RM is an alkyl group of 1 to 4 carbon atoms, wherein A is either cyano or formyl or a group of formula 7, wherein R is hydrogen, alkyl or alkoxy of 1 to 4 carbon atoms, fluorine, is chlorine, bromine or trifluoromethyl and Y is an oxygen atom or the combination of H and OH, and wherein B is hydrogen or a group of formula 8, wherein R 1 represents hydrogen, fluorine, chlorine or bromine and Z represents an oxygen atom of 10 or two alkoxy groups each having 1-8 carbon atoms or an alkylene-dioxy group having 2-8 carbon atoms and 2-3 carbon atoms in the chain between the two oxygen atoms, with the limitation that if A is cyano or formyl B is not hydrogen, and the salts of pharmaceutically acceptable acids with such compounds in which A is not cyano or formyl and B is not hydrogen, and wherein Y and Z are both oxygen. A compound according to claim 1, characterized in that Y is an oxygen atom. Compound according to claim 2, characterized in that Z is an oxygen atom. Compound according to claim 3, characterized in that R "is methyl. 5. A compound according to claim 3 or 4, characterized in that R 'is fluorine. 6. The compound 4- (4-benzoyl-4-methylpiperidin) -p-fluorobutyrophenone and its salts with pharmaceutically acceptable acids. 7. The compound 4- (4-p-fluorobenzoyl-4-methylpiperidino) -p-fluorobutyrophenone and its salts with pharmaceutically acceptable acids. 8. The compound 4- (4-p-chlorobenzoyl-4-methylpiperidino) -p-fluorobutyrophenone and its salts with pharmaceutically acceptable acids, 9. The compound 4- (4-p-methylbenzoyl-4-methylpiperidino) -p-fluorobutyrophenone and its salts with pharmaceutically acceptable acids, 80 05 89 0, 10, The compound 4- (4-p-methoxybenzoyl-4-methylpiperidino) -p-fluorobutyrophenone and its salts with pharmaceutically acceptable acids, 5 11, The compound 4- (4-m-trifluoromethyl-benzoyl-4-methylpiperidino) p-fluorobutyrophenone and its salts with pharmaceutically acceptable acids. A compound according to claim 1, characterized in that A is cyano and B is a group according to formula 8 wherein Z] O represents two alkoxy groups or an alkylenedioxy group. Compound according to any one of claims 1 to 12, characterized in that B is hydrogen, A compound according to any one of claims 1 to 12, characterized in that A is formyl and B is a group according to formula 8 wherein Z represents two alkoxy groups or an alkylenedioxy group, Compound according to claim 1, characterized in that Y is a combination of H and OH. 16, Pharmaceutical composition containing one or more compounds of formula 1, wherein R, R1 and R "have the meanings given previously and Y and Z are both oxygen atoms. Pharmaceutical preparation according to claim 16, characterized in that it contains 0.5 to 25 mg of active substance per unit dose. A process for preparing a compound according to claim 3, characterized in that (a) a compound of formula 2, wherein R and R "have the meanings given previously, is reacted with a compound of formula 4, wherein R 'has the meanings given previously and 30. is a halogen atom or a reactive leaving group, (b) 4-cyano-piperidine alkylates with a compound of the formula XQ, wherein X is a halogen or a reactive leaving group and Q is a group of the formula 8, wherein Z represents two alkoxy groups or an alkylenedioxy group and R '35 has the meanings given previously, the cyano ketal thus formed is alkylated in the presence of a strong base with an alkyl halide of 80 0589 0 with 1-4 carbon atoms react the compound of formula 2 thus formed in which A is cyano, Z represents two alkoxy groups or an alkylenedioxy group and R 'and RM have the meanings given previously, with a unsubstituted phenyl lithium or phenylmagnesium halide, and the ketal group is hydrolyzed in the compound of formula 1 thus formed, in which Z is two alkoxy groups or an alkylenedioxy group, (c) a compound of formula 3, wherein A is cyano, Z10 represents two alkoxy groups or an alkylenedioxy group and R 'and R "have the meanings given previously, with a sterically hindered hydride reducing to the corresponding compound of formula 3 wherein A is formyl aldehyde reacts with a substituted or unsubstituted phenyl lithium or phenyl-magnesium halide, and the compound of formula 1 thus formed in which Y is the combination of H and OH oxidizes the secondary alcohol to a ketone and the ketal grouping to a ketone group hydrolyzes, and (d) optionally converting a base thus obtained with a pharmaceutically acceptable acid into a salt, or releasing the base from a salt thus obtained, 19, Process for the preparation of a compound of formula 1, wherein R, R * and R "have the meanings given previously and Y and Z are both oxygen atoms, in a manner known per se for analogous compounds. 8005890 L ·· 9, 'o (ch «), - C ~ ((S) ~ R' H 2 RHI R. Λ X. $, Φ o <“ '·>' J & - {/ AR "'X., 9 «I 5 I ch3 b <5) - ¢ - 7 - © =« '8 80 05 89 0 t Richaidson-Merrell Ine., In Cincinnati, Ohio, United States of America