NO147672B - ANALOGUE PROCEDURE FOR PREPARING N-ARYL-N- (1-L1-4-PIPERIDINYL) -ARYLACETAMIDES - Google Patents

Description

The present invention relates to analogue methods for the production of new, therapeutically active N-aryl-N-(1-1A-4-piperidinyl)-arylacetamides. In the past it has been discovered that some N-aryl-N-(4-piperidinyl)amides have analgesic properties. A number of such components can be found in the following references: US-PS 3,164,600 and

ABOUT. , 77, 34349a (1972).

Among other things, the antiarrhythmic compounds in the present compound differ from such known compounds in the manner in which the arylacetamide group is linked to the 4-position in the piperidine nucleus.

The new N-aryl-N-(1-L^-4-piperidinyl)arylacetamides produced according to the present invention can be structurally represented by the following formula:

and the pharmaceutically acceptable acid addition salts thereof, wherein

L^" means alkyl with 1-10 carbon atoms, cycloalkyl and cycloalkylalkyl where cycloalkyl has 3-6 atoms and alkyl has 1-6 atoms or alkenyl with 3-6 C atoms;

Ar denotes phenyl, mono- or disubstituted phenyl, pyridinyl or 2-pyrimidinyl, in which each substituent in the mono- or disubstituted phenyl is halogen or alkyl with 1-6 carbon atoms;

Ar<1> means phenyl, mono- or disubstituted phenyl, or thienyl, wherein each substituent in the mono- or disubstituted phenyl is halogen, alkyl of 1-6 carbon atoms, hydroxy or alkyloxy of 1-6 carbon atoms; and

X means hydrogen, alkyloxycarbonyl with 1-6 carbon atoms or alkyloxymethyl with 1-6 carbon atoms,

whereby when Ar and Ar"<*>" both mean phenyl or substituted phenyl

and X means hydrogen, L<1> cannot mean cycloalkyl with from 5 to 6 carbon atoms.

The compounds of formula (I) can be prepared by

introducing a suitable L<1->substituent into a suitable compound of formula (I-a)

according to known N-alkylation procedures.

The aforementioned N-alkylation can be easily carried out by reacting (I-a) with a suitable reactive ester of the formula L<1->Y, (V), where L<1> is as defined above and where Y is a suitable reactive ester radical such like for example. halogen or a sulfonyl radical such as e.g. methanesulfonyl or 4-methyl-benzenesulfonyl. The aforementioned reaction can be carried out in the usual way, e.g. by mixing the reactants together under reflux in a suitable reaction-inert organic solvent such as e.g. a lower alkanol, e.g. methanol, ethanol, propanol, butanol etc. alcohols; an aromatic hydrocarbon, e.g. benzene, methylbenzene, dimethylbenzene, etc.; a ketone, e.g. 4-methyl-2-pentanone; an ether, e.g. 1,4-dioxane, 1,1'-oxybisethane and the like; N,N-dimethylformamide; nitrobenzene; beer. To bind the acid released during the reaction, a suitable base can be added, such as e.g. sodium or potassium carbonate or bicarbonate or an organic base, e.g. N,N-Diethylethanamine. A small amount of alkali metal iodide, e.g. potassium iodide, can be added to increase the reaction rate, especially when the reactive ester (V) is a chloride or bromide.

When L<1> in the compounds (I) is alkyl, cycloalkyl or cycloalkyl-lower alkyl and when the carbon atom linked to the nitrogen in piperidine has at least one hydrogen atom linked to it, the introduction of said L can be carried out just as easily by catalytic hydrogenation of a mixture of an appropriate aldehyde or ketone corresponding to the alcohol L -OH

and a compound of the formula (I-a) in the presence of a suitable catalyst such as e.g. palladium-on-coal. To improve the selectivity in the hydrogenation reaction, a small amount of a suitable catalyst poison can be added to the mixture, such as e.g. thiophene.

Yet another method of preparing the compounds of formula (I) consists of acylating an appropriate N-aryl-1-L^-4-piperidinamine of formula (VII) with an appropriate arylacetyl halide of formula (III) according to well-known N-acylation procedures as described above for the preparation of (IV) starting from (II) and (III).

Acylation of (VII) with (III) can be carried out using known N-acylation procedures, e.g. by stirring the reactants together and refluxing in a suitable reaction-inert organic solvent, preferably in the presence of a suitable base. Suitable solvents that can be used include e.g. aromatic hydrocarbons such as e.g. benzene, methylbenzene and dimethylbenzene and halogenated hydrocarbons such as trichloromethane. Suitable bases include e.g. alkali metal carbonates and hydrogen carbonates, <1>alkali metal amides such as sodium amide, and organic bases such as e.g. pyridine and N,N-diethylethanamine.

When Ar<1> in the compounds (I) is a substituted phenyl group which has as substituents one or two hydroxyl groups alone or together with other substituents, it is required to protect the said hydroxyl groups in the corresponding starting materials (III) with a suitable protecting group such as a lower alkyloxycarbonyl, after which a corresponding derivative of (I) is provided and the protecting group is easily removed by alkaline hydrolysis using e.g. dilute aqueous alkali.

The compound according to the invention can be converted into pharmaceutically acceptable acid addition salts by treatment with a suitable acid such as e.g. an inorganic acid such as a hydrohalic acid, e.g. hydrochloric acid, hydrobromic acid, etc. and sulfuric acid, nitric acid, phosphoric acid etc., or an organic acid such as e.g. acetic acid, propanoic acid, 2-hydroxy-acetic acid, 2-hydroxypropanonic acid, 2-oxopropanonic acid, propanonedioic acid, butanedioic acid, (Z)-2-butenedioic acid, (E)-2-butenedioic acid, 2-hydroxybutanedioic acid, 2,3- dihydroxybutanedione acid, 2-hydroxyl-1,2,3-propanetricarboxylic acid, benzoic acid, 3-phenyl-2-propenonic acid, α-hydroxybenzeneacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, cyclohexanesulfamic acid, 2-hydroxybenzoic acid, 4- amino-2-hydroxybenzoic acid, etc. acids. The salt form can be converted to the free base by treatment with alkali.

The intermediate products used as starting materials in the preceding preparations, several of which are known compounds, can be prepared in the following way:

The intermediates of formula (I-a) can usually be prepared by starting from a piperidine derivative of formula (II) where Ar and X are as previously defined and where P is a suitable protecting group such as e.g. phenylmethyl, lower alkyloxycarbonyl or a phenylmethoxycarbonyl by first acylating (II) with a suitable arylacetyl halide of formula (III) and then preferably the chloride to then eliminate the protecting group P of the thus obtained (IV) by methods known per se:

The elimination of the protecting group P can be carried out by known methods. When the protecting group is phenylmethyl or phenylmethoxycarbonyl, it can be readily removed by catalytic hydrogenation using a suitable catalyst, e.g. palladium-on-charcoal, and when the protecting group is lower alkyloxycarbonyl, the elimination can easily be carried out using a strong mineral acid, e.g. hydrochloric acid, hydrobromic acid or sulfuric acid, and alkaline hydrolysis is easily carried out by using alcoholic alkali, e.g. potassium hydroxide in 2-propanol.

The intermediate products of formula (II) where X is hydrogen, (II-a), are easily prepared in the following way. A 4-piperidin-one of the formula (VIII) which in the 1-position has a suitable protecting group P, is subjected to a condensation reaction with a suitable arylamine (IX) e.g. by refluxing the reactants with stirring with azeotropic water removal in a suitable organic solvent, preferably an aromatic hydrocarbon such as benzene, methylbenzene or dimethylbenzene, in the presence of a suitable acid such as e.g. 4-methylbenzenesulfonic acid, acetic acid, hydrochloric acid, etc. The resulting Schiff base (X) is then reduced with a suitable reducing agent such as e.g. sodium borohydride or by catalytic hydrogenation using e.g. platinum oxide catalyst to provide the corresponding N-aryl-4-piperidine-amine (II-a).

The aforementioned reactions are illustrated more clearly by the following reaction nucleus:

Intermediates of formula (VII) where X is hydrogen, (VII-a), are easily prepared starting from (II-a) by first eliminating the protecting group P in the usual manner to provide an N-aryl-4-piperidinamine with the formula (XI) and then the L^-substituent is introduced as described above, for the preparation of (I) starting from (I-a).

When L in the intermediates (VII-a) is a methyl group, (VII-a-1), they can be provided directly by a reduction of the intermediate (II-a) where P is a lower alkyloxycarbonyl group, (II-a-2 ), with a suitable reducing agent such as e.g. lithium aluminum hydride. The aforementioned reactions are illustrated by the following reaction nucleus:

Intermediates of formula (II) where X is lower alkoxycarbonyl, (II-b), can be prepared in the following way: 1-phenylmethyl-4-piperidinone (XII) is reacted with a suitable arylamine (IX) and an alkali metal cyanide, e.g. potassium cyanide in an aqueous organic carboxylic acid system such as acetic acid or an aqueous lower alkanol in the presence of an equivalent of an inorganic acid such as hydrochloric acid whereby the introduction of the nitrile function and the amine function is carried out in the 4-position of the piperidine nucleus, giving an intermediate with the formula (XIII).

The nitrile (XIII) is then converted to the amide (XIV) by acid hydrolysis. A concentrated strong, aqueous, inorganic acid can advantageously be used for this purpose, such as hydrochloric acid, phosphoric acid and preferably sulfuric acid. The amide (XIV) is further hydrolysed to provide the corresponding carboxylic acid (XV) using the known amide-to-acid hydrolysis methods, e.g. by treating (XIV) with a dilute strong acid, e.g. hydrochloric or sulfuric acid or by alkaline hydrolysis using a suitable base, e.g. sodium or potassium hydroxide. The provided carboxylic acid (XV) is in turn converted into its metal salt, preferably the sodium salt (XVI), by reaction with alkali, e.g. sodium hydroxide. The carboxylic acid (XV) does not necessarily need to be isolated or purified, but can be used as an impure mixture for the preparation of (XVI), or the salt can be provided directly when the alkaline hydrolysis is carried out.

The salt (XVI) is then converted into the desired one

ester (II-b) where P is phenylmethyl (II-b-1) by reaction with a suitable halogen-lower alkane (XVII) in a suitable solvent such as e.g. hexamethylphosphoric triamide.

The aforementioned reactions are illustrated more clearly by the following reaction scheme:

The intermediates of the formula (II-b) where P is lower alkyloxycarbonyl or phenylmethoxycarbonyl (II-b-2) are easily prepared from (II-b-1) by eliminating the protecting phenylmethyl group and then introducing into the thus obtained ( XIX) the lower alkyloxycarbonyl or phenylmethoxycarbonyl group according to known methods, e.g. by converting e.g.

(XIX) with a suitable lower alkyl or phenylmethylcarbonhalidate or directly by reacting (II-b-1) with a lower alkyl or phenylmethylcarbonhalidate after which the phenylmethyl group in (II-b-1) is replaced by the desired lower alkyloxycarbonyl or phenylmethoxycarbonyl group.

The intermediates of the formula (VII) where X is lower alkyloxycarbonyl (VII-b) are suitably prepared by introducing the L "'' group into an intermediate (XIX) according to the methods described above.

The intermediates of the formula (II) and (VII) where X is lower alkyloxymethyl, (II-c) and (VII-c) can be prepared as follows: A suitable lower alkyl ester of the formula (II-b) is reduced with a suitable reducing agent as like for example. sodium dihydro-bis(2-methoxyethoxy)aluminate (Red-Al) in a suitable organic solvent such as e.g. benzene or with lithium borohydride to provide 4-piperidinemethanol of formula (XX). The aforementioned (XX) is subjected to an O-alkylation reaction with a suitable alkylating agent. The O-alkylation step can be carried out by reacting (XX) with a suitable halogen-lower alkane or di-(lower alkyl)sulphate in a suitable organic solvent such as e.g. benzene, methylbenzene, dimethylbenzene, tetrahydrofuran, etc. in the presence of a suitable quaternary ammonium salt such as N,N,N-triethylbenzenemethanaminium chloride which gives the desired intermediate (II-c). The intermediate products

(VII-c) can be prepared by first eliminating the protecting group in (II-c) and then introducing the L<1->substituent in the thus obtained intermediate (XXI) according to the methods described earlier.

Otherwise, the intermediates (VII-c) can also be prepared by reducing a suitable alkyl ester with the formula (VII-b) to the corresponding 4-piperidinemethanol (XXII) in a similar way as described above for the preparation of (XX) starting from (II-b ), to then subject (XXII) to an O-alkylation reaction with a suitable lower alkylating agent according to the methods indicated to prepare (II-c) starting from (XX).

The aforementioned methods are illustrated in

the following:

The compounds of formula (I) and their pharmaceutically acceptable acid addition salts exhibit excellent antiarrhythmic properties and are useful in normalizing irregular heart rhythms. The antiarrhythmic effect in the compounds according to the invention is illustrated by the following experiment with dogs.

The tests were performed under neuroleptanalgesia

(1 ml/10 kg body weight of fentanyl (N-phenyl-N-[1-(2-phenyl-ethyl)-4-piperidinyl]propanamide) (0.4 mg/ml) and droperidol (1-[1-[ 4-(4-fluorophenyl)-4-oxobutyl]-1,2,3,6-tetrahydro-4-pyridinyl]-1,3-dihydro-2H-benzimidazol-2-one) (20 mg/ml)). About. 16 hours after ligation of the posterior descending branch of the left coronary artery, the dogs exhibited a multifocal ventricular arrhythmia.

The test compounds were administered intravenously after a control period of 30 min., and the following criteria were applied:

0 : no effect.

+ : reduction of the number of premature beats and an increase of the number of normal beats by at least 30% compared to the control value.

++ : reduction of the number of premature beats and an increase of the number of normal beats by at least 50% compared to the control value.

+++ : normalization of the heart rhythm or reduction of the number of premature beats and the number of normal beats by at least 75% compared to the control value.

The results of this experiment are reproduced in the following tables.

For the sake of comparison, trials have been carried out with the compound described in claim 2 of US-PS 3,869,463, also known as compound R 5630. These trials conclude that compound R 5630 is totally inactive, even at exceptionally high dosages, in the sample described here.

The following examples illustrate the invention. Unless otherwise stated, all parts are parts by weight.

Examples I to XXIX describe the preparation of intermediates.

Example I

A mixture of 19 parts of 1-(phenylmethyl)-4-piperidinone, 11.8 parts of 3-pyridinamine, 120 parts of methylbenzene and a small amount of 4-methylbenzenesulfonic acid is stirred and refluxed for 5 hours. (The reaction vessel is equipped with a reflux condenser and a water separator). After the calculated amount of water has been separated, the solvent is evaporated. The oily residue is dissolved in 800 parts of 2,2<1->oxybispropane and evaporated again which gives 27 parts of N-[1-phenylmethyl)-4-piperidinylidene]-3-pyridinamine as a yellow-brown oil.

To a stirred solution of 27 parts of N-[1-(phenylmethyl)-4-piperidinylidene]-3-pyridinamine in 40 parts of ethanol, 3.8 parts of sodium borohydride are added in portions. After the addition is complete, the mixture is heated to 50°C. The solvent is evaporated. The oily residue is dissolved in 150 parts hydrochloric acid IN and filtered. The filtrate is made alkaline with ammonium hydroxide and extracted with methylbenzene. The organic layer is dried over magnesium sulphate, filtered and evaporated. The solid residue is washed with 2,2'-oxybispropane and dried which gives 14 parts of N-[1-(phenylmethyl)-4-piperidinyl]-3-pyridinamine with melting point 131-133°C as a beige, amorphous powder.

A mixture of 20 parts N-[1-(phenylmethyl)-4-piperidinyl]-3-pyridinamine, 160 parts methanol, 30 parts water and 12 parts concentrated hydrochloric acid solution is hydrogenated at normal pressure and with a temperature between 22 and 39 °C, in the presence of 7 parts palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen has been taken up, the hydrogenation is stopped. The catalyst is filtered off, and the filtrate is evaporated. The oily residue dissolves in water. This solution is made alkaline with ammonium hydroxide, saturated with solid potassium carbonate and then extracted with methylbenzene. The extract is dried over potassium carbonate and evaporated. -The solid residue is recrystallized from a mixture of 40 parts of benzene and 32 parts of 1,1<1->oxybisethane, which gives 3 parts of N-(4-piperidinyl)-3-pyridinamine with a melting point of 127-129°C.

Example II

A mixture of 171.2 parts of ethyl 4-oxo-1-piperidinecarboxylate, 159.5 parts of 4-chlorobenzenamine, 1520 parts of anhydrous methylbenzene and a few crystals of 4-methylbenzenesulfonic acid is stirred and refluxed for 7 hours. (The reaction vessel is equipped with a reflux cooler and a water separator). The methylbenzene is evaporated and the oily residue is distilled in vacuum, which gives 192 parts of oily ethyl 4-[(4-chlorophenyl)imino]-1-piperidine carboxylate with boiling point 171-176°C at 0.4 mm pressure.

Example III

By repeating the procedure from e.g. II and using equivalent amounts of a suitable arylamine instead of 4-chlorobenzenamine, the following compounds are prepared:

Example IV

A mixture of 171 parts of ethyl 4-oxo-1-piperidine carboxylate, 162 parts of 2,6-dichlorobenzeneamine, 800 parts of dimethylbenzene and 1 part of 4-methylbenzenesulfonic acid is stirred and refluxed with a water separator. The reaction mixture is evaporated, giving 250 parts of ethyl 4-[(2,6-dichlorophenyl)imino]-1-piperidinecarboxylate as a residue.

Example V

To a hot solution of 192 parts of ethyl 4-[(4-chlorophenyl)-imino]-1-piperidinecarboxylate in 560 parts of methanol, 23.5 parts of sodium borohydride are added in portions at 50°C over the course of 1 hour. After the addition has ended, the mixture is stirred at the same temperature for 2 hours. The methanol evaporates.

The solid residue is heated with approx. 600 parts water and the product is extracted with benzene. The extract is dried over magnesium sulfate and evaporated. The oily residue solidifies when treated with 2,2'-oxybispropane. The solid is filtered off and dried, which gives 122 parts of ethyl 4-[(4-chlorophenyl)amino]-1-piperidine carboxylate with a melting point of 115-118°C.

Example VI

Using the method that is

given in ex. V and using an equivalent amount of an appropriate ethyl 4-arylimino-1-piperidine carboxylate, the following compounds are prepared:

Example VII

30 parts of sodium borohydride are added in portions to a stirred solution which is boiled under reflux of 250 parts of ethyl 4-[(2,6-dichlorophenyl)imino]-1-piperidine carboxylate in 160 parts of methanol and 160 parts of 2-propanol. After the addition has ended, stirring is continued at the reflux temperature for 1 hour. The hot reaction mixture is poured into water and the product is extracted with methylbenzene. The extract is dried and evaporated. The residue is crystallized from a mixture of 160 parts of 2,2'-oxybispropane and 160 parts of petroleum ether, which gives 96 parts of ethyl 4-[(2,6-dichlorophenyl)amino]-1-piperidine carboxylate with a melting point of 107.2-116.6 °C.

Example VIII

A mixture of 45 parts of ethyl 4-[(2,6-dimethylphenyl)-imino]-1-piperidinecarboxylate, 0.3 parts of platinum dioxide in 160 parts of methanol is hydrogenated at normal pressure and at a temperature of between 24 and 35°C. After the calculated amount of hydrogen has been taken up, the hydrogenation is stopped. The catalyst is filtered off and the filtrate is evaporated. The oily residue is distilled which gives 30 parts of an oily free base of ethyl 4-[(2,6-dimethylphenyl)amino]-1-piperidinecarboxylate with melting point 148-153°C at 0.01 mm pressure. From this distillate, the hydrochloride salt is prepared in the usual way in 1,1<1->oxybisethane. The precipitated solid salt is filtered off and dried, which gives 28.5 parts of ethyl 4-[(2,6-dimethylphenyl)amino]-1-piperidinecarboxylate hydrochloride with a melting point of 195.5°C.

A mixture of 10 parts of ethyl 4-[(2,6-dimethylphenyl)-amino]-1-piperidinecarboxylate and 135 parts of hydrobromic acid solution 48% is stirred at a temperature of between 80 and 110°C until the evolution of gaseous carbon dioxide ends (after approx. 1 hour). The red colored reaction mixture is evaporated in vacuo. The residue is taken up in 56 parts of methylbenzene and the latter is evaporated again. The evaporation is repeated in a mixture of 24 parts of 2-propanone and 40 parts of methylbenzene. The resulting semi-solid residue is triturated in 80 parts of hot 2-propanone and upon cooling the solid product precipitates. It is filtered off and washed respectively with small amounts of absolute ethanol and 2-propanone and dried which gives 13 parts of N-(2,6-dimethylphenyl)-4-piperi-

Example IX

A mixture of 7 parts ethyl 4-(2-pyrimidinylamino)-1-piperidine carboxylate and 120 parts hydrobromic acid solution

48% is stirred and boiled under reflux for 2 hours. The reaction mixture is evaporated and the residue taken up in water. The whole is made alkaline with dilute sodium hydroxide solution while cooling in an ice bath. The product is extracted with dichloromethane. The extract is dried, filtered and evaporated. The solid residue is stirred with 2,2'-oxybispropane. The product is filtered off and converted to the hydrochloride salt in 2-propanol. The salt from is filtered and crystallized from ethanol, which gives 2 parts of N-(4-piperidinyl)-2-pyrimidinamine dihydrochloride hemihydrate with a melting point of 268.5°C.

Example X

A mixture of 32.5 parts of methyl 4-(phenylamino)-1-(phenylmethyl)-4-piperidine carboxylate and 200 parts of methanol is hydrogenated at normal pressure and at room temperature with 5 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen has been taken up, the catalyst is filtered off and the filtrate is evaporated. The oily residue solidifies by scraping in 2,2'-oxybispropane. The product is filtered off and dried under vacuum, which gives 20 parts (85%) of methyl 4-(phenylamino)-4-piperidine carboxylate with a melting point of 139.1°C.

Example XI

To a stirred solution of 58 parts of ethyl 4-[(4-chlorophenyl)amino]-1-piperidinecarboxylate in 240 parts of benzene is added dropwise a solution of 46.2 parts of benzene acetyl chloride in 80 parts of benzene at a temperature between 40 and 70°C . After the addition has ended, the mixture is stirred and boiled under reflux for 6 hours and 15 minutes. The reaction mixture is cooled and filtered. The filtrate is washed with water, sodium hydrogen carbonate solution and water, after which it is dried and evaporated in a vacuum. The residue is crystallized from 1,1'-oxybisethane, which gives 47 parts of ethyl 4-[N-(4-chlorophenyl)-N-(phenylacetyl)amino]-1-piperidinecarboxylate with a melting point of 108°C.

Example XII

Using the method from ex. XI

and by using equivalent amounts respectively of an appropriate

ethyl 4-arylamino-1-piperidine carboxylate and a suitable aryl acetyl chloride instead of ethyl 4-[(4-chlorophenyl)amino]-1-piperidine carboxylate and benzene acetyl chloride, the following compounds are prepared:

Example XIII

To a stirred solution of 8 parts of ethyl 4-[(2,6-dimethylphenyl)amino]-1-piperidinecarboxylate in 4 parts of pyridine and 80 parts of benzene, 7.7 parts of benzene acetyl chloride in 40 parts of benzene are added dropwise. After the addition has ended, the whole is heated to reflux and stirred at the reflux temperature for 3 hours and 45 minutes. The reaction mixture is cooled and filtered. The benzene phase is washed with water and then with sodium hydrogen carbonate solution and with water. After evaporation, an oily residue is provided which solidifies on trituration with 1,1'-oxybisethane and gives 5 parts of ethyl 4-[N-(2,6-dimethylphenyl)-N-(phenylacetyl)amino]-1-piperidinecarboxylate with melting point 106 °C.

Example XIV

To a stirred solution of 15 parts of ethyl 4-[(4-chlorophenylamino]-1-piperidinecarboxylate, 5.4 parts of N,N-diethylethanamine and 160 parts of benzene, 11.07 parts of 4-methoxybenzene acetyl chloride are added dropwise at a temperature of between 32 and 40°C. After the addition is complete, the whole is stirred and refluxed for 3 hours. The reaction mixture is cooled and filtered. The filtrate is washed with water, sodium bicarbonate solution and water, dried, filtered and evaporated in vacuo. The oily residue is crystallized from a mixture of 56 parts of 1,1'-oxybisethane and 40 parts of hexane.The crude solid product is filtered off and recrystallized from a mixture of benzene and 1,1<1->oxybisethane to give 3 parts of ethyl-4 -{N-(4-chlorophenyl)-N-[(4-methoxyphenyl)acetyl]amino}-1-piperidine carboxylate with melting point 137°C.

Example XV

A mixture of 20 parts of ethyl 4-[N-(2-chlorophenyl)-N-(phenylacetyl)amino]-1-piperidine carboxylate and 300 parts of hydrobromic acid solution 48% is stirred and refluxed for 1 hour and 10 minutes. The hydrobromic acid solution of 48% is removed under vacuum and water and then sodium hydroxide solution are added to the remainder. The free base is extracted with trichloromethane. The trichloromethane is dried and evaporated. The solid residue is washed with 1,1'-oxybisethane and dried, which gives 10.6 parts of N-(2-chlorophenyl)-N-

(4-piperidinyl)benzeneacetamide with melting point 135.5°C.

Example XVI

By following the procedure that is reproduced in ex. XV and using the equivalent amount of an appropriate ethyl 4-[N-aryl-N-(arylacetyl)amino]-1-piperidinecarboxylate in place of ethyl 4-[N-(2-chlorophenyl)-N-(phenylacetyl) amino]-1-piperidine carboxylate which is used in ex. XV the following compounds are produced:

Example XVII

A mixture of 5 parts of ethyl 4-[N-(2,6-dimethylphenyl)-N-(phenylacetyl)amino]-1-piperidinecarboxylate in 60 parts of hydrobromic acid solution 48% is heated until the evolution of carbon dioxide has ceased. The heating continues for 15 min. to a temperature between 80 and 120°C. The reaction mixture is evaporated. The solid residue is washed with methylbenzene over 2-propanone and dried, which gives 4.1 parts of N-(2,6-dimethylphenyl)-N-(4-piperidinyl)-benzeneacetamide hydrobromide with a melting point of 251.5°C.

Example XVIII

A mixture of 10 parts of ethyl 4-[N-(4-chlorophenyl)-N-(phenylacetyl)amino]-1-piperidine carboxylate and 125 parts of glacial acetic acid previously saturated with gaseous hydrogen bromide is heated for 9 hours and 4 5 min. at 6 2°C with stirring. The reaction mixture is cooled and the glacial acetic acid is evaporated in vacuo. The semi-solid residue is taken up in 150 parts water, made alkaline

with concentrated sodium hydroxide solution and the product is extracted with trichloromethane. The extract is dried over sodium sulfate and evaporated. The oily residue is triturated in 56 parts of 1,1'-oxybisethane and the solid, unpurified free base is filtered off.

It is converted to the hydrochloride salt in the usual way in 1,1'-oxybisethane and 2-propanone which gives 4 parts of N-(4-chlorophenyl)-N-(4-piperidinyl)benzeneacetamide hydrochloride with a melting point of 206.5°C.

Example xix

By following the procedure from e.g. XVIII oa using an equivalent amount of a suitable ethyl 4-[N-aryl-N-(aryl-acetyl)amino]-1-piperidine carboxylate as starting material, the following compounds are prepared: N-(2,6-dimethylphenyl)-N -(4-piperidinyl)-2-thiophenacetamide; m.p. 128°C; N-(4-chlorophenyl)-N-(4-piperidinyl)-2-thiophenacetamide hydrochloride; m.p. 201.5°C;

4-chloro-N-(4-chlorophenyl)-N-(4-piperidinyl)4-benzeneacetamide hydrochloride; m.p. 222°C; and

N-(4-chlorophenyl)-4-methyl-N-(4-piperidinyl)benzeneacetamide; m.p. 121°C.

Example XX.

To a refluxed and stirred mixture consisting of 48 parts of 1-(1-methylethyl)-4-piperidinone,

1 part 4-methylbenzenesulfonic acid and 540 parts methylbenzene add-

dropwise a solution of 30 parts benzenamine in 90 parts methylbenzene. After the addition has ended, stir the mix-

none and boil under reflux for 3 hours with a water separator. The reaction mixture is evaporated, giving 72 parts of N-[1-(1-methylethyl)-4-piperidinylidene]benzenamine as a residue.

To a stirred and heated (30-40°C) solution

of 72 parts of N-[1-(1-methylethyl)-4-piperidinylidene]benzenamine in 480 parts of methanol, 20 parts of sodium borohydride are added in portions. After the addition has ended, stirring is continued overnight at room temperature. The reaction mixture is evaporated and the residue is dissolved in water. The solution is extracted with 4-methyl-2-pentanone. The extract is washed with water and acidified with dilute hydrochloric acid solution. The aqueous acid phase is made alkaline with dilute sodium hydroxide solution to pH 9 and the product is extracted with 4-methyl-2-pentanone. The extract is washed with water, dried, filtered and evaporated. The residue is distilled (boiling point 135-140°C at 0.2 mm pressure) and the distillate is crystallized from petroleum ether, which gives 21 parts of 1-(1-methylethyl)-N-phenyl-4-piperidinamine with a melting point of 69.3°C.

Example XXI

To a warm (40°C) solution of 12 parts of potassium hydroxide in 240 parts of 2-propanol, 21 parts of ethyl-4-{N-(4-chlorophenyl)-N-[(4-methoxyphenyl)acetyl]amino} are added at once -1-piperidine carboxylate and the mixture is stirred and refluxed for 21 hours. The reaction mixture is cooled, filtered and the filtrate is evaporated. The residue is taken up in water and the aqueous solution is made acidic with dilute hydrochloric acid solution. The acidic solution is washed with 1,1'-oxybisethane, made alkaline with sodium hydroxide and the free base is extracted with methylbenzene. The latter is dried, filtered and evaporated. The rest dissolves

in 1,1'-oxybisethane and after crystallization, 10 parts of N-(4-chlorophenyl)-4-methoxy-N-(4-piperidinyl)benzeneacetamide with melting point 129.5°C are obtained.

Example XXII

To a stirred and warm (40°C) solution of 12 parts of potassium hydroxide in 200 parts of 2-propanol, 21 parts of ethyl-4-{N-(4-chlorophenyl)-N-[(3-methoxyphenyl)acetyl] are added at once -amino}-1-piperidine carboxylate and the mixture is stirred and refluxed for 17 hours. The reaction mixture is cooled, filtered and evaporated. The semi-solid residue is acidified with dilute hydrochloric acid solution, washed with 1,1'-oxybisethane and the aqueous, acidic phase is made alkaline with sodium hydroxide solution. The free base is extracted with trichloromethane. The extract is dried and evaporated. The residue is crystallized from a mixture of 1,1'-oxybisethane and hexane which gives 7.8 parts of N-(4-chlorophenyl)-3-methoxy-N-(4-piperidinyl)benzeneacetamide with a melting point of 85.7°C.

Example XXIII

A mixture of 52 parts of 2-bromopropane, 19 parts of N-(4-piperidinyl)-3-pyridinamine, 33.3 parts of sodium carbonate, 3 parts of potassium iodide and 720 parts of 4-methyl-2-pentanone is stirred and refluxed for 24 hours . The reaction mixture is cooled and filtered. The filtrate is evaporated. The residue is purified by column chromatography over silica gel using methanol as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 2,2<1->oxybispropane which gives 1.5 parts of N-[1-(1-methylethyl)-4-piperidinyl]-3-pyridinamine with a melting point of 100.7%.

Example XXIV

Applying the procedure of Example 25 and using equivalent amounts of a suitable bromide and of a suitable 4-(acetylamino)-4-X-piperidine respectively as starting materials and carrying out the reaction in the indicated solvent, the following compounds are provided in form of its free bases or in the form of the hydrochloride salt after treatment with hydrochloric acid:

Example XXV

To a stirred mixture of 15 parts of N-(4-chlorophenyl)-4-piperidinamine, 12 parts of N,N-diethylethanamine in 130 parts of benzene is added dropwise to a solution of 10.3 parts of 3-bromo-l-popene in 70 parts benzene. After the addition has ended, the whole thing is first stirred for 20 hours and 30 minutes. at room temperature and then for 40 min. at reflux temperature. The reaction mixture is cooled, filtered and the filtrate is evaporated. The remainder is taken up in 1,1'-oxybisethane and treated with activated charcoal. The latter is filtered off and 1,1<1->oxybisethane is evaporated again, which gives 2.9 parts of N-(4-chlorophenyl)-1-(2-propenyl)-4-piperidineamine with a melting point of 90°C.

Example XXVI

To a warm (approx. 40°C) and stirred mixture of 5 parts N-(2,6-dimethylphenyl)-4-piperidinamine, 5 parts sodium carbonate, some crystals of potassium iodide in 120 parts benzene are added dropwise to a solution of 5.1 parts of 1-iodopropane in 80 parts of benzene. After the addition has ended, stirring is continued for 40 hours at the reflux temperature. The reaction mixture is cooled and 50 parts of water are added. The organic layer is separated, dried and evaporated in vacuo. The oily residue is distilled, which gives 10.2 parts of N-(2,6-dimethylphenyl)-1-propyl-4-piperidinamine with boiling point 135°C at 0.2 mm pressure.

Example XXVII

To 0.5 parts of a solution of 2 parts thio-

fen in 40 parts ethanol, 2 parts cyclopentanone are added, 5.5

parts N-(4-piperidinyl)-2-pyrimidinamine and 120 parts methanol. The mixture is hydrogenated at normal pressure and at room temperature with 2 parts palladium-on-charcoal 10%. After the calculated amount of hydrogen has been taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is taken up in 4-methyl-2-pentanone and a small amount of trichloromethane. The mixture is washed twice with dilute sodium hydroxide solution, dried, filtered and evaporated. The residue is crystallized from 2,2'-oxybispropane. The product is filtered off and dried, which gives 2.3 parts of N-(1-cyclopentyl-4-piperidinyl)-2-pyrimidinamine with a melting point of 118°C.

Example XXVIII

To 0.5 parts of a solution of 2 parts thiophene

in 40 parts of ethanol, 4 parts of 2-propanone, 4.5 parts of N-(4-piperidinyl)-2-pyrimidinamine and 120 parts of methanol are added. The mixture is hydrogenated at normal pressure and at room temperature with 2 parts palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen has been taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is dissolved in trichloromethane. The solution is washed with dilute sodium hydroxide solution and with water, dried, filtered and evaporated to give 3 parts of N-[1-(1-methylethyl)-4-piperidinyl]-2-pyrimidinamine as a residue.

Example XXIX

A solution of 13 parts ethyl-4-[N-(2,6-dimethylphenyl) amino]-1-piperidinecarboxylate in 40 parts of 1,1'-oxybisethane. After the addition has ended, refluxing and stirring are continued for 20 hours. The reaction mixture is cooled to 5°C and 7 parts of water are added, the precipitate which forms is filtered off, washed on the filter with 1,1<1->oxybisethane and the filtrate is evaporated. The oily residue is distilled, which gives 5.8 parts of N-(2,6-dimethylphenyl)-1-methyl-4-piperidinamine with a boiling point of 90-93°C at 0.003 mm pressure. On standing, the distillate solidifies and gives solid N-(2,6-dimethylphenyl)-1-methyl-4-piperidinamine with a melting point of 45°C.

The following examples describe the production of final products.

Example 1

To a stirred suspension of 5 parts of N-(4-chloro-phenyl)-N-(4-piperidinyl)benzeneacetamide, 5 parts of sodium carbonate and a few crystals of potassium iodide in 200 parts of butanol, 4 parts of 2-bromopropane are added dropwise at room temperature. After the addition has ended, the mixture is stirred and refluxed for 20 hours. Then another portion of 4 parts 2-bromopropanone is added and stirring and refluxing are continued for a further 19 hours. The reaction mixture is cooled, filtered and the filtrate is evaporated. From the oily, free base, the hydrochloride salt is prepared in the usual way in a 1,1'-oxybisethane and 2-propanone. The precipitated solid salt is filtered off and crystallized from a mixture of 2-propanone and 2-propanol, yielding 2 parts of N-(4-chlorophenyl)-N-[1-(1-methylethyl)-4-piperidinyl]benzeneacetamide hydrochloride with melting point 26 3°C.

Example 2

By following the procedure from e.g. 1 and by using an equivalent amount of an appropriate bromide and of an appropriately large N-aryl-N-(4-piperidinyl)arylacetamide, the following compounds are prepared as hydrochloride salts:

Example 3

To a stirred and warm (40°C) mixture of 5 parts of N-(4-chlorophenyl)-N-(4-piperidinyl)benzeneacetamide, 5 parts of sodium carbonate, some crystals of potassium iodide and 200 parts of n-butanol, 3.75 parts of bromocyclopentane are added and the mixture is stirred and refluxed for 21 hours and 30 minutes. Another portion of 5 parts bromocyclopentane is then added and the stirring and refluxing are continued for a further 30 hours. The reaction mixture is cooled, filtered and the filtrate is evaporated.

The oily residue solidifies by trituration in 1,1'-oxybisethane. The solid product is filtered off and crystallized from 1,1'-oxybisethane, which gives 1.1 parts of N-(4-chlorophenyl)-N-(1-cyclopentyl-4-piperidinyl)benzeneacetamide with a melting point of 139.5°C.

Example 4

By following the procedure from e.g. 3 and using equivalent amounts of a suitable bromide and of a suitable N-aryl-N-(4-piperidinyl)arylacetamide respectively as starting materials, the following compounds are prepared:

Example 5

To a mixture which is stirred and refluxed and which consists of 5 parts N-(4-chlorophenyl)-N-(4-piperidinyl)benzeneacetamide, 5 parts sodium bicarbonate and 200 parts benzene, 6.7 parts (bromomethyl)cyclopropane and the stirring and reflux continue for 23 hours. The reaction mixture is cooled and filtered. The filtrate is evaporated. The semi-solid residue is dissolved in a mixture of benzene and 1,1'-oxybisethane. The precipitated impurities are filtered off and the filtrate is evaporated again. From the oily, free base, the hydrochloride salt is prepared in the usual way and after crystallization of the impure salt from a mixture of trichloromethane and 1,1'-oxybisethane yields 1.5 parts of N-(4-chlorophenyl)-N-[1-(cyclopropylmethyl) )-4-piperidinyl]benzeneacetamide hydrochloride with a melting point of 224°C.

Example 6

To a stirred solution of 5 parts of N-(4-chlorophenyl)-N-(4-piperidinyl)benzeneacetamide, 3.8 parts of N,N-diethylethanamine in 200 parts of benzene, 5 parts of 3-bromo-l-prop-ene are added in portions . After the addition has ended, the mixture is heated for 21 hours to a temperature of between 50 and 60°C. The reaction mixture is cooled and filtered. The filtrate is washed with water, sodium bicarbonate solution and water, dried over potassium carbonate and evaporated. The oily residue is converted to the hydrochloride salt in 1,1<1->oxybisethane and 2-propanone which gives 4 parts of N-(4-chlorophenyl)-N-[1-(2-propenyl)-4-piperidinyl]benzeneacetamide hydrochloride with a melting point of 225.5°C.

Example 1

By following the procedure from e.g. 6 and by using an equivalent amount of an appropriate N-aryl-N-(4-piperidinyl)-arylacetamide in place of the N-(4-chlorophenyl)-N-(4-piperidinyl)benzeneacetamide used in this example , the following compounds are prepared: N-(2,6-dimethylphenyl-N-[1-(2-propenyl)-4-piperidinyl]-2-thiophene-acetamide hydrochloride with melting point 203.5°C and N-(2,6- dimethylphenyl)-N-[1-(2-propenyl)-4-piperidinyl]benzeneacetamide hydrochloride with melting point 214°C.

Example 8

To a hot suspension of 5 parts of N-(4-chlorophenyl)-N-(4-piperidinyl)benzeneacetamide, 5 parts of sodium carbonate and some

few crystals of potassium iodide in 200 parts of n-butanol are added 4

splits 2-chloro-2-methylpropane at a temperature of between 30 and 40°C. The mixture is stirred and refluxed for 140 hours, during which time 35 parts of 2-chloro-2-methylpropane are added in portions as follows: after a reflux time of 15

hours, 4 parts of 2-chloro-2-methylpropane are added, after 8 hours 10 parts and after 16 hours 11 parts and finally after 47 hours 10 parts. The reaction mixture is cooled, filtered and the filtrate is evaporated. The semi-solid residue is dissolved in a mixture of methylbenzene, dimethoxyethane and 1,1'-oxybisethane. The solution is filtered to remove any impurities and the filtrate is evaporated again. From the oily residue, the hydrochloride salt is prepared in the usual way in 1,1'-oxybisethane which, after recrystallization of the impure, solid salt from 2-propanone, yields 0.9 parts of N-(4-chlorophenyl)-N-[1-( 1,1-dimethylethyl)-4-piperidinyl]benzeneacetamide hydrochloride with melting point 221°C.

Example 9

A mixture of 4 parts iodoethane, 5 parts N-(2,6-dimethylphenyl)-N-(4-piperidinyl)benzeneacetamide, 5 parts sodium carbonate, a few crystals of potassium iodide in 200 parts benzene is stirred and refluxed for 23 hours. The reaction mixture is filtered hot and the filtrate is evaporated in vacuo. The solid residue is crystallized from 1,1'-oxybisethane, which gives 2 parts

N-(2,6-dimethylphenyl)-N-(1-ethyl-4-piperidinyl)benzeneacetamide

with melting point 86.5oc.

Example 10

By following the procedure from e.g. 9 and using an equivalent amount of an appropriate N-aryl-N-(4-piperidinyl)arylacetamide in place of N-(2,6-dimethylphenyl)-N-(4-piperidinyl)benzeneacetamide the following compounds were prepared : 2-chloro-N-(4-chlorophenyl)-N-(1-ethyl-4-piperidinyl)benzeneacetamide hydrochloride; m.p. 234.6°C; N-(4-chlorophenyl)-N-(1-ethyl-4-piperidinyl)-3-methylbenzeneacetamide; m.p. 78.5°C;

N-(4-chlorophenyl)-N-(1-ethyl-4-piperidinyl)-4-methylbenzeneacetamide; m.p. 50°C and

N-(4-chlorophenyl)-N-(1-ethyl-4-piperidinyl)-4-fluorobenzeneacetamide; m.p. 6 2.3°C.

Example 11

To a mixture of 5 parts of 4-chloro-N-(4-chlorophenyl)-N-(4-piperidinyl)benzeneacetamide, 5 parts of sodium carbonate, 0.4 parts of potassium iodide in 200 parts of butanol which is refluxed with stirring, is added 4, 7 parts 1-iodopropane and the mixture is stirred and refluxed for 22 hours. Another portion of 4.5 parts of 1-iodopropane is then added and refluxing and stirring are continued for 27 hours and 30 minutes. The reaction mixture is cooled, filtered and the filtrate is evaporated. The semi-solid residue is dissolved in methylbenzene. The solution is filtered to remove any impurities and the filtrate is evaporated again. The residue is crystallized from 1,1<1->oxybisethane at -10°C which gives 0.9 parts of 4-chloro-N-(4-chlorophenyl)-N-(1-propyl-4-piperidinyl)benzeneacetamide with melting point 118 .6°C.

Example 12

To a stirred solution of 4 parts N-(4-chlorophenyl)-N-(4-piperidinyl)benzeneacetamide and 3 parts N,N-diethylethanamine

4 parts of 1-iodopropane are added in portions to 200 parts of benzene and the mixture is stirred and refluxed for 47 hours. Another portion of 4 parts 1-iodopropane is then added and the stirring and refluxing are continued for a further 20 hours and 20 minutes. The reaction mixture is cooled and filtered.

The filtrate is washed with water, dried and evaporated in vacuo. From the oily, free base, the hydrochloride salt is prepared in the usual way in 1,1'-oxybisethane. The precipitated solid salt is filtered off and dried, which gives 3.5 parts of N-(4-chlorophenyl)-N-(1-propyl-4-piperidinyl)benzeneacetamide hydrochloride with a melting point of 233.5°C.

Example 13

By using the procedure from e.g. 12 and by using an equivalent amount of a suitable iodoalkane and a suitable N-aryl-N-(4-piperidinyl)arylacetamide respectively instead of 1-iodopropane and N-(4-chlorophenyl)-N-(4-piperidinyl)benzeneacetamide was the following compounds prepared: N-(2,6-dimethylphenyl)-N-(1-ethyl-4-piperidinyl)-2-thiophenacetamide hydrochloride of melting point 258°C; N-(4-chlorophenyl)-N-(1-ethyl-4-piperidinyl)-2-thiophenacetamide hydrochloride; m.p. 220.5°C; N-(4-chlorophenyl)-N-(1-ethyl-4-piperidinyl)benzeneacetamide hydrochloride; m.p. 215°C;

4-chloro-N-(4-chlorophenyl)-N-(1-ethyl-4-piperidinyl)benzeneacetamide hydrochloride; m.p. 224°C and

N-(4-chlorophenyl)-N-(1-propyl-4-piperidinyl)2-thiophenacetamide hydrochloride, m.p. 241°C

Example 14

A mixture of 4.5 parts N-(1-cyclopentyl-4-piperidinyl)-2-pyrimidinamine, 3.4 parts 3-methylbenzeneacetyl chloride,

2 parts sodium carbonate and 180 parts dimethylbenzene are stirred and boiled under reflux for 17 hours. A further 9 parts of 3-methylbenzeneacetyl chloride are added dropwise. After the addition has ended, stirring is continued for 67 hours at reflux temperature. The reaction mixture is cooled, water is added and the layers are separated. The organic phase is extracted with dilute hydrochloric acid solution. The combined aqueous phases are washed with benzene and made alkaline with dilute sodium hydroxide solution while the mixture is cooled in an ice bath. The product is extracted twice with trichloromethane. The combined extracts are dried, filtered and evaporated. The residue is converted to the ethanedioate salt in 2-propanol. The salt is filtered off and crystallized twice: first from ethanol and then from methanol, which gives 1 part of N-(1-cyclopentyl-4-piperidinyl)-3-methyl-N-(2-pyrimidinyl)benzeneacetamide ethanedioate with a melting point of 204.1°C .

Example 15

By following the procedure from e.g. 14 and by

using equivalent amounts of a suitable N-aryl-4-piperidinamine and of a suitable arylacetyl chloride respectively as starting materials, the following compounds were produced in base form or in acid addition salt form after treatment with a suitable acid:

Example 16

A mixture of 5 parts of methyl 1-(1 methylethyl)-4-(phenylamino)-4-piperidine carboxylate, 24 parts of 4-chlorobenzene acetyl chloride, 4 parts of sodium carbonate and 180 parts of dimethylbenzene is stirred and refluxed for 32 hours. The reaction mixture is cooled, washed with a dilute sodium hydroxide solution and extracted with a dilute hydrochloric acid solution: 3 layers are provided. The oil and water phase are combined and made alkaline with a dilute sodium hydroxide solution. The product is extracted with 4-methyl-2-pentanone. The extract is washed with water, dried, filtered and evaporated. The residue is converted to the ethanedioate salt in 2-propanol. The salt is filtered off and crystallized from a mixture of 2-propanol and 2,2<1->oxybispropane which gives 5 parts (48%) of methyl-4-[N-(4-chlorophenyl)acetyl-N-phenylamino]-l- (1-Methylethyl)-4-piperidine carboxylate ethanedioate with melting point 154.2°C.

Example 17

By using the procedure from e.g. 16 and using equivalent amounts of a suitable 4-aryl-amino-4-piperidine carboxylate and a suitable arylacetyl chloride respectively as starting material, the following compounds were provided in the form of a free base or in the form of an acid addition salt after treatment with the appropriate acid:

Example 18

To a stirred mixture of 4.4 parts of 1-(1-methylethyl)-N-phenyl-4-piperidinamine, 5.3 parts of sodium carbonate and 180 parts of benzene, 5 parts of benzene acetyl chloride are added dropwise. After the addition has ended, stirring is continued overnight at reflux temperature. The reaction mixture is cooled, washed with water, sodium bicarbonate solution and again with water, dried, filtered and evaporated. The residue is converted to the hydrochloride salt in 2,2'-oxybispropane and 2-propanol. The salt formed is filtered off and crystallized from a mixture of 2-propanol and 2,2<1->oxybispropane which gives 2.5 parts of N-[1-(1-methylethyl)-4-piperidinyl]-N-phenylbenzeneacetamide hydrochloride of m.p. 184.4°C.

Example 19

By using the procedure from e.g. T5 and using equivalent amounts of a suitable large N-aryl-4-piperidinamine and of a suitable arylacetyl chloride respectively as starting material, the following compounds were provided in base form or in the form of an acid addition salt after treatment with the appropriate acid:

Example 20

A suspension of 1.25 parts sodium amide i

56 parts of benzene are stirred under a nitrogen atmosphere and heated at a temperature of 40°C. A solution of 6 parts of N-(4-chlorophenyl)-1-(1-methylethyl)-4-piperidineamine in 56 parts of benzene is then added dropwise to the mixture. After the addition has ended, the mixture is stirred and refluxed for 16 hours and 45 minutes. The mixture is cooled to 25°C and a mixture of 7.8 parts of 3,4-dichlorobenzeneacetyl chloride in 88 parts of benzene is added. After stirring and refluxing for a further 2 hours, the reaction mixture is cooled and 80 parts water is added. The whole is acidified with diluted hydrochloric acid solution. The aqueous, acidic phase is made alkaline with sodium hydroxide solution and the free base is extracted with trichloroethane. The extract is dried, filtered and evaporated. The residue is dissolved in a mixture of 80 parts of 1,1'-oxybisethane and 120 parts of hexane. The solution is cooled overnight at -10°C, some impurities are filtered off and the filtrate is evaporated again. The residue is dissolved in 120 parts of 1,1'-oxybisethane, treated with activated carbon, filtered and evaporated.

The last residue is crystallized from hexane at -10°C giving 2.2 parts of 3,4-dichloro-N-(4-chlorophenyl)-N-[1-(1-methylethyl)-4-piperidinyl]benzeneacetamide with melting point 101.7°C.

Example 21

By using the procedure from e.g. 20 and using equivalent amounts of a suitable N-aryl-4-piperidinamine and a suitable arylacetyl chloride respectively as starting material, the following compounds were provided in base form or in acid addition salt form after treatment with the appropriate acid: 4-bromo-N-(4 -chlorophenyl)-N-[1-(1-methylethyl)-4-piperidinyl]-benzeneacetamide; m.p. 118.1°C;

4-chloro-N-(2,6-dimethylphenyl)-N-[1-(1-methylethyl)-4-piperidinyl]-benzeneacetamide hydrochloride; m.p. 268.2°C;

N-(4-chlorophenyl)-4-(1-methylethyl)-N-[1-(1-methylethyl)-4-piperidinyl]-benzeneacetamide; m.p. 104.9°C.

Example 22

5 parts of 4-chloro-N-(4-chlorophenyl)-N-[1-(1-methylethyl)-4-piperidinyl]benzeneacetamide are dissolved in a mixture of 60 parts of 1,1'-oxybisethane and 16 parts of 2-propanone. The resulting solution is acidified with an excess of 2-propanol which has previously been saturated with gaseous hydrogen chloride. The precipitated salt is filtered off and dried, which gives 7.5 parts of 4-chloro-N-(4-chloro-phenyl)-N-[1-(1-methylethyl)-4-piperidinyl]benzeneacetamide hydrochloride with a melting point of 266.6 °C.

Example 23

From 6 parts of N-[1-(1-methylethyl)-4-piperidinyl]-N-phenyl-2-thiophenacetamide (E)-2-butenedioate, the free base is released in the usual way with dilute sodium hydroxide solution. The product is extracted with trichloromethane. The extract is washed with water, dried, filtered and evaporated. The residue is converted to the ethanedioate salt in 2-propanol. The salt is filtered off and dried, which gives 3.2 parts of N-[1-(1-methylethyl-4-piperidinyl]-N-phenyl-

2-thiophenacetamide ethanedioate with melting point 167.4°C.

Example 24

From an aqueous solution of 2.8 parts of N-(2,6-dimethyl-phenyl)-N-(1-propyl-4-piperidinyl)-2-thiophenacetamide dihydrochloride, the free base is liberated by alkalization with sodium bicarbonate solution. The free base is extracted with 1,1'-oxybisethane. The extract is dried and evaporated. The oily residue is dissolved in 56 parts of hexane and after cooling to -10°C the free base is precipitated. It is filtered off and dried, which gives 1.6 parts of N-(2,6-dimethylphenyl)-N-(1-propyl-4-piperidinyl)-2-thiophenacetamide with melting point 6 2.5°C.

Example 25

From 3.9 parts of N-(1-cyclopentyl-4-piperidinyl)-3-methyl-N-(3-pyridinyl)benzeneacetamide (E)-2-butenedioate, the free base is liberated in the usual way with dilute sodium hydroxide solution. After extraction with 2,2'-oxybispropane, the latter is washed with water, dried, filtered and evaporated. The residue is converted to the ethanedioate salt in ethanol. The salt is filtered off and crystallized from a mixture of ethanol and 2,2'-oxybispropane which gives 3 parts of N-(1-cyclopentylD-4-piperidinyl)-3-methyl-N-(3-pyridinyl)benzeneacetamide ethanedioate with a melting point of 192.6 °C.

Example 26

A mixture of 50 parts of 4-(£enylamino)-1-(phenylmethyl)-4-piperidinecarboxamide in 600 parts of concentrated hydrochloric acid solution is refluxed for 16 hours. After cooling, the reaction mixture is concentrated under reduced pressure to a volume of 400 parts, after which a precipitate is formed. It is filtered off, washed with water and 2-propanone and dried, giving 43 parts of 4-(phenylamino)-1-(phenylmethyl)-4-piperidinecarboxylic acid dihydrochloride, mp 261-263°C (decomposition).

A mixture of 19 parts of 4-(phenylamino)-1-(phenylmethyl)-4-piperidinecarboxylic acid dihydrochloride, 14.4 parts of sulfuric acid and 64 parts of ethanol is stirred and refluxed for 16 hours. The solvent is decanted. The rest is dissolved in water. The aqueous solution is made alkaline with ammonium hydroxide and extracted with a mixture of methylbenzene and 2,2'-propane. The combined organic layers are dried over magnesium sulphate, filtered and evaporated. The oily residue is dissolved in 200 parts of 2,2<1->oxybispropane and gaseous hydrogen chloride is added to the solution.

The precipitated hydrochloride is filtered off, washed with 2-propanol, filtered again and dried, which gives 11.5 parts of ethyl 4-(phenyl-amino)-1-(phenylmethyl)-4-piperidinecarboxylate dihydrochloride with melting point 212-214, 4°C.

To a stirred solution which is boiled under reflux

and which consists of 101.4 parts of ethyl 4-(phenylamino)-1-(phenylmethyl)-4-piperidine carboxylate in 640 parts of dry benzene, a solution of 172 parts of sodium dihydro-bis(2-methoxy-ethoxy)aluminate 70% is added dropwise in benzene in 160 parts of dry benzene. After the addition has ended, stirring is continued for 2 hours and 30 minutes. at 80°C. The reaction mixture is cooled, poured into ice water, made alkaline with sodium hydroxide solution and the product is extracted with benzene. The extract is washed twice with water, dried, filtered and evaporated. The residue is converted to the hydrochloride salt in 2-propanol and, after cooling, the product is filtered off. It is boiled once more in acetonitrile and the salt is filtered off again after cooling. The free base is released in the usual way. After extraction with 1,1'-oxybisethane, the latter is washed with water, dried and evaporated to give 56.6 parts of 4-(phenylamino)-1-(phenylmethyl)-4-piperidinemethanol as an oily residue.

To a solution of 32 parts of 4-(phenylamino)-1-(phenylmethyl)-4-piperidinemethanol in 90 parts of benzene is added 0.2 parts of N,N,N-triethylbenzenemethanaminium chloride and 150 parts of sodium hydroxide solution 60%. After vigorous stirring, 10.9 parts of dimethylsulphate are added dropwise at a temperature below 30°C. After the addition has ended, the stirring is continued at room temperature first for 2 hours and 30 minutes and then, after the addition of another portion of 2.6 parts of dimethylsulphate, for 1 hour and 30 minutes, the reaction mixture is cooled in ice water and 200 parts of water are added. The organic phase is separated and the aqueous phase is extracted with benzene. The combined organic phases are washed with water, dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and 3% methanol saturated with ammonia as eluent. The pure fractions are collected and the eluent is evaporated somewhat

which gives 24.8 parts of 4-(methoxymethyl)-N-phenyl-1-(phenylmethyl)-4-piperidinamine as a residue.

A mixture of 10 parts of 4-(methoxymethyl)-N-phenyl-1-(phenylmethyl)-4-piperidinamine and 200 parts of acetic acid is hydrogenated at normal pressure and room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen has been taken up, the catalyst is filtered off and the filtrate is evaporated. The oily residue is dissolved in water, cooled and made alkaline with ammonium hydroxide. The product is extracted with trichloromethane. The extract is washed with water, dried, filtered and evaporated. The oily residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) saturated with gaseous ammonia as eluent. The pure fractions are collected and the eluent evaporated to give 4.5 parts of 4-(methoxymethyl)-N-phenyl-4-piperidinamine as an oily residue.

A mixture of 10 parts of 2-bromopropane, 9 parts of 4-(methoxymethyl)-N-phenyl-4-piperidinamine, 4.9 parts of N,N-diethylethanamine and 72 parts of N,N-dimethylacetamide is stirred and boiled during the to-back race in 10.25 hours. After cooling, the formed N-N-diethylethanamine hydrobromide is filtered off, and the filtrate is diluted with water. The product is extracted with methylbenzene. The extract is washed well with water, dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (90:10) as eluent).

The pure fractions are collected and the eluent evaporated to give 5.7 parts (42.6%) of 4-(methoxymethyl)-1-(1-methylethyl)-N-phenyl-4-piperidine as an oily residue.

To a stirred mixture of 5.5 parts of 4-(methoxymethyl)-1-(1-methylethyl)-N-phenyl-4-piperidinamine in 56 parts of benzene is added dropwise a solution of 13.8 parts of benzene acetyl chloride in 45 parts of benzene at 26 -32°C. After the addition has ended, the stirring is continued first for 1 hour at 26-32°C and for a further 3 hours and 40 minutes at 38-55°C. After cooling, the precipitated product is filtered off and converted to the hydrochloride salt in a mixture of 2-propanol and 2-propanone (in a volume ratio of 5:1). The salt is filtered off and dissolved in absolute ethanol. After standing for 72 hours at room temperature, the precipitated product is filtered off and washed with a small amount of 2-propanone and dried, yielding 1.05 parts of N-[4-(methoxymethyl)-1-(1-methyl-ethyl)- 4-piperidinyl]-N-phenylbenzeneacetamide hydrochloride with melting point 2 4 9.1°C.

Example 27

8 parts of [4-(2-chloro- 2-oxoethyl)phenyl]ethyl carbonate. After the addition is complete, the mixture is heated to the reflux temperature and stirring is continued for 1 hour at the reflux temperature. After cooling, the precipitated product is filtered off and stirred for 30 min. in a mixture of alkaline water and trichloromethane. The teams are separated. The organic phase is dried, filtered and evaporated. The oily residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (in the volume ratio 90:10) as eluent. The pure fractions are collected and the eluent evaporated to give 5.5 parts of ^4-£2-{(4-chlorophenyl)-[1-(1-methylethyl)-4-piperidinyl]amino}-2-oxoethyljphenyl^ethylcarbonate as a oily residue.

A mixture of 5.5 parts of ^4-j^ 2-{ (4-chlorophenyl) [ 1-(1-methylethyl)-4-piperidinyl]amino}-2-oxoethyl phenyl^ethyl carbonate and 50 parts of sodium hydroxide solution 10% is stirred for 90 min. at 45°C. The reaction mixture is cooled to room temperature and acidified with acetic acid to pH 5.5-6. The product is extracted with trichloroethane. The extract is dried, filtered and evaporated. The oily residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (in the volume ratio 80:20) as eluent. The pure fractions are collected and the eluent is evaporated. The oily residue was converted to the hydrochloride salt of 4-methyl-2-pentanone. The salt is filtered off and dried in vacuo for 12 hours at 60°C, which gives 1.9 parts of N-(4-chlorophenyl)-4-hydroxy-N-[1-(1-methylethyl)-4-piperidinyl]benzeneacetamide monohydrochloride with m.p. 24 2.9°C.

Example 2 8

A mixture of 8 parts 2-propanone and 9.9 parts N-(4-chlorophenyl)-N-(4-piperidinyl)-benzeneacetamide hydrochloride in 16 9 parts methanol is hydrated at normal pressure and room temperature with 2 parts 10% palladium -on-charcoal catalyst.

After the calculated amount of hydrogen has been taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is taken up in a mixture of 2-propanone and 1,1<1->oxobispropane and precipitated as the hydrochloride salt. The product is filtered off and dried and 6.3 parts of N-(4-chlorophenyl)-N-[1-methylethyl)-4-piperidinyl]-benzeneacetamide hydrochloride with a melting point of 262.3°C are obtained.

Claims (4)

1. Analogous method for the preparation of therapeutically active N-aryl-N-(4-piperidinyl)-arylacetamides of the formula: and pharmaceutically acceptable acid addition salts thereof, where L"*" means alkyl with 1-10 carbon atoms, cycloalkyl and cycloalkylalkyl where cycloalkyl has 3-6 carbon atoms and alkyl has 1-6 carbon atoms or alkenyl with 3-6 C atoms; Ar means phenyl, mono- or disubstituted phenyl, pyridinyl or 2-pyrimidinyl, wherein each substituent in the mono- or disubstituted phenyl is halogen or alkyl of 1-6 carbon atoms; Ar"<*>" means phenyl, mono- or disubstituted phenyl, or thienyl, wherein each substituent in the mono- or disubstituted phenyl is halogen, alkyl of 1-6 carbon atoms, hydroxy or alkyloxy of 1-6 carbon atoms; and X means hydrogen, alkyloxycarbonyl with 1-6 carbon atoms or alkyloxymethyl with 1-6 carbon atoms, whereby when Ar and Ar"<*>" both mean phenyl or substituted phenyl and X means hydrogen, L"<*>" cannot mean cycloalkyl with from 5-6 carbon atoms, characterized in that a) a compound with the formula N-alkylated by reaction with a suitable reactive ester of formula L^-Y, where Y means a suitable reactive ester group, in a suitable for the reaction inert organic solvent, suitably in the presence of a base, or b) a compound of the formula (I) is prepared where L"*- means alkyl, cycloalkyl or cycloalkylalkyl and the carbon atom which is bound to the piperidine nitrogen has at least one hydrogen atom bound to it , by catalytic hydrogenation of a mixture of a suitable aldehyde or ketone corresponding to the alcohol L -OH and a compound of formula (I-a) in the presence of a suitable catalyst, or c) a compound of the formula is acylated with a suitable arylacetyl halide of the formula in a suitable reaction-inert organic solvent, preferably in the presence of a base, and, when Ar in the final product (I) means mono- or dihydroxyphenyl, a suitable protecting group is introduced into this or these hydroxyl groups in the starting compound (III), and when the final product is prepared , these protecting groups are removed by alkaline hydrolysis and, if desired, the prepared compounds of formula (I) are converted into their pharmaceutically acceptable acid addition salts. 2. Analogous process according to claim 1 for the production of N-(4-chlorophenyl)-N-[1-(1-methylethyl)-4-piperidinyl]benzeneacetamide and pharmaceutically acceptable acid addition salts thereof, characterized in that N-(4-chlorophenyl) -N-(4-piperidinyl)benzeneacetamide is reacted with 2-bromopropane and, if desired, a pharmaceutically acceptable acid addition salt of the product is produced. 3. Analogous process according to claim 1 for the production of N-(4-chlorophenyl)-N-(1-ethyl-4-piperidinyl)benzeneacetamide and pharmaceutically acceptable acid addition salts thereof, characterized in that one reacts N-(4-chloro-phenyl) -N-(4-piperidinyl)benzeneacetamide with iodoethane and, if desired, prepare a pharmaceutically acceptable acid addition salt of the product. 4. Analogous method according to claim 1 for the production of 3-chloro-N-(1-cyclohexyl-4-piperidinyl)-N-phenylbenzeneacetamide and pharmaceutically acceptable acid addition salts thereof, characterized in that one reacts 1-cyclohexyl-N- phenyl-4-piperidinamine with 3-chlorobenzeneacetyl chloride and, if desired, preparing a pharmaceutically acceptable acid addition salt of the product.