FI61482C - PROCEDURE FOR THE FRAMEWORK OF THERAPEUTIC NUTRITION N-ARYL-N- (1-L-4-PIPERIDINYL) -ARYLACETAMIDER - Google Patents

Description

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Patents and Register of Publications of the United States of America (32) (33) (31) Pyy <l «« y ttuoiktut — eugird prtor »t« t 23 * 09 * 75 i2.O8.76 USA (US) 615131, 713756 (71) Janssen Pharmaceutica Naamloze Vennootschap, Turnhoutsebaan 30,

Beerse, Belgium-Belgien (BE) (72) Stefan Sanczuk, Vosselaar, Hubert K. Fr. Hermans, Gierle, Belgium-Belgier. (BE) (7M Oy Kolster Ab (5M Process for the preparation of new, therapeutically useful N-aryl-N- (11'-piperidinyl) -arylacetamides - For the preparation of N-aryl-N- ( piperidinyl) -arylacetami: ier

The novel N-aryl-N- (1-L-4-piperidinyl) -arylacetamides are useful in the treatment of irregular heartbeat.

A few N-aryl-N- (4-piperidinyl) amides with analgesic activity have been known in the past. These compounds are described in U.S. Patent No. 3,164,600 and C.A., 77, 34,349a ('. 372). Among other differences, the antiarrhythmic compounds of the invention differ from these known compounds in that they have an arylacetamide group attached at the 4-position of the piperidine ring.

The invention relates to a process for the preparation of novel therapeutically useful N-aryl-N- (4-piperidinyl) arylacetamides of the formula (I): N-C-CH2-Ar (I)

Ar 2,61482 and pharmaceutically acceptable acid addition salts thereof, wherein L is (C 1 -C 6) -alkyl, (C 8 -C 8) -cycloalkyl, (C 8 -C 8) -cycloalkyl-lower alkyl or lower alkenyl; Ar is phenyl, mono- or di-substituted phenyl, pyridinyl or 2-pyrimidinyl, wherein the substituent on said mono- or disubstituted phenyl is halogen or lower alkyl; Ar 1 is phenyl, mono- or di-substituted phenyl or thienyl, said substituent on said mono- or di-substituted phenyl being halogen, lower alkyl, hydroxy or lower alkyloxy; and X is hydrogen, lower alkyloxycarbonyl or lower alkyloxymethyl, wherein when Ar and Ar 1 both represent phenyl or substituted phenyl and X is hydrogen, then L is not (C 8 -C 8) cycloalkyl.

The term "(C 1 -C 4) -alkyl" as used in the definition of the substituent L means a straight or branched chain saturated hydrocarbon radical having from 1 to 10 carbon atoms, such as, for example, methyl, ethyl, 1-methylethyl, propyl, 1-methylpropyl , butyl, 2-methylbutyl, 1,1-dimethylethyl, pentyl, hexyl, heptyl, decyl and the like alkyl; the term "lower alkyl" as used herein means a straight or branched chain alkyl radical having from 1 to 6 carbon atoms such as, for example, methyl, ethyl, 2-methylethyl, propyl, butyl, pentyl, hexyl and the like; the phrase "lower alkenyl" means an alkenyl radical having 3 to 6 carbon atoms, such as, for example, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl and the like; the term "cycloalkyl" means cyclic hydrocarbon radicals having from 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; and the term "halogen" generally means halogens having an atomic weight of less than 127, i. fluorine, chlorine, bromine and iodine.

The process according to the invention is characterized in that a) the formula (1-a)

HOC

- I 2

The compound of Ar is N-alkylated in a manner known per se, preferably by reacting said compound (Ia) with a reactive ester of formula LY, wherein Y is a reactive ester radical, in a reaction-inert organic solvent, preferably in the presence of a base, or 3 61482 b ) of formula (1-b) * j ~ y '.

\ / \ Ij 1 (l-b) N- 'N-C-CH2 ~ Ar1

To prepare a compound of formula Ar wherein R 1 is (C 1 -C 6) -alkyl, (C 8 -C 6) -cycloalkyl or (C 5 -C 8) -cycloalkyl-lower alkyl and on a carbon atom attached to a piperidine nitrogen , is at least one nitrogen atom, a catalytic hydrogenation of a mixture of an aldehyde or ketone corresponding to the alcohol L 1 -OH and a compound of formula (Ia) in the presence of a suitable catalyst, or c) a compound of formula (VII) \ Λνη <vii>

Ar is acylated with the appropriate arylacetyl halide of formula (III) 0 halo-C-CH 2 -Ar 1 (III) in a suitable reaction-inert organic solvent, preferably in the presence of a base, and in case Ar 1 in the final compound (Ib) has mono- or dihydroxyphenyl , preferably a suitable protecting group is added to said hydroxyl or hydroxyls in the starting compound (III), and after the final product is prepared, said protecting groups are removed by alkaline hydrolysis, and d) if desired, the resulting compound of formula (I) or (Ib) is converted into a pharmaceutically acceptable acid addition salt. The starting material (1-a) is obtained according to the following reaction scheme in which Ar, Ar "* and X have the same meaning as above, and P is a protecting group such as, e.g., phenylmethyl, lower alkyloxycarbosyl or phenylmethoxycarbonyl.

4,61482 P-N ~ ^ X + halo-C-CH ^ Ar1 acylotic_ ^

Ar (II) (III) αχ protecting group ff, PQi5tam_inen_> N-C-CH, -Ar I 2

Ar (iV)

On-Lh, - *, · L 2 (1-a)

The acylation of compound (II) with compound (III) can be carried out following the N-acylation methods known per se, e.g. by stirring and refluxing the reaction components in a suitable inert organic solvent, preferably in the presence of a base. Suitable solvents include, for example, aromatic hydrocarbons such as benzene, methylbenzene and dimethylbenzene, and halogenated hydrocarbons such as trichloromethane. Suitable bases include, for example, alkali metal carbonates and bicarbonates, alkali metal amides such as sodium amide, and organic bases such as, for example, pyridine and N, h-diethylethanamine.

Removal of the protecting group P can be carried out in a manner known per se. When the protecting group is phenylmethyl or phenylmethoxycarbonyl it is easily removed by catalytic hydrogenation using a suitable catalyst, e.g. palladium on carbon, and when the protecting group is lower alkyloxycarbonyl it can be easily removed by acidic or alkaline hydrolysis. Acid hydrolysis can be performed using a strong mineral acid, e.g. hydrochloric, hydrobromic or sulfuric acid, and alkaline hydrolysis can be performed using an alcoholic alkali, e.g. potassium hydroxide in 2-propanol.

The N-alkylation according to process variant a) can be conveniently carried out by reacting compound (Ia) with a reactive ester of formula L 1 -Y, (V) in which ΐΛ is as defined above and Y is a reactive ester radical such as halogen or a sulfonyl radical such as methanesulfonyl or 4-methylbenzenesulfonyl. The reaction may be carried out in a conventional manner, e.g. by stirring and refluxing the reaction components in a suitable inert organic solvent such as a lower alkanol, e.g. methanol, ethanol, propanol, butanol and the like; in an aromatic hydrocarbon, e.g. benzene, methylbenzene, dimethylbenzene and the like, a ketone, e.g. 4-methyl-2-pentanone; in ether, e.g., 1,4-dioxane, 1,1'-oxybisethane and the like; N, N-dimethylformamide; nitrobenzene; and the like. A suitable base such as sodium or potassium carbonate or bicarbonate or an organic base such as vet, Ν-diethylethanamine may be added to scavenge the acid liberated during the reaction. A small amount of alkali metal iodide, e.g. potassium iodide, can be added to improve the reaction rate, especially when the reactive ester (V) is chloride or bromide.

According to process variant b), the coupling of L 1 can be carried out by catalytic hydrogenation of a mixture of a suitable aldehyde or diketone corresponding to the alcohol L 2 -OH and a compound of formula (I-a) in the presence of a suitable catalyst such as palladium on carbon. To improve the selectivity of the hydrogenation reaction, a small amount of a suitable catalyst poison, such as thiophene, may be added to the mixture.

According to process variant c), the N-aryl-1H-4-piperidinamine of formula (VII) is acylated with an arylacetyl halide of formula (III) by a well-known N-acylation process described above for the preparation of compound (IV) starting from compounds (II) and (III). ).

X + (III) - »(I-b) N_Λΐ ™

Ar <VII> 6 61482

When Ar 1 in compounds (Ib) represents a substituted phenyl group in which one or two hydroxyl groups are substituted, either alone or in combination with other substituents, it is expedient to protect said hydroxyl groups in the corresponding starting materials (III) with a suitable protecting group, such as lower alkyloxycarbonyl, to give the corresponding derivative of the compound (Ib) and its protecting group can be easily removed by alkaline hydrolysis using e.g. dilute alkali.

The obtained compounds can be converted into pharmaceutically acceptable acid addition salts by treatment with a suitable acid such as, for example, an inorganic acid such as hydrohalic acid, hydrochloric acid, hydrobromic acid and the like, and sulfuric acid, nitric acid, phosphoric acid and the like; with an organic acid such as acetic, propanone, 2-hydroxyacetic, 2-hydroxypropanone, 2-oxopropanone, propanedione, butanedione, (Z) -2-butenedione, (E) - 2-butenedione, 2-hydroxybutanedione, 2,3-dihydroxybutanedione, 2-hydroxy-1,2,3-propanetricarboxylic, benzo, 3-phenyl-2-propenone, N-hydroxybenzeneacetic , methanesulfonic, ethanesulfonic, benzenesulfonic-4-methylbenzenesulfonic, cyclohexanesulfamine, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids. Similarly, the salt form can be converted to the free base form by treatment with an alkali.

The intermediates used as starting materials in the above reaction, many of which are known compounds, can be prepared as follows.

Intermediates of formula (II) wherein X is hydrogen, (II-a) are suitably obtained as follows. The 4-piperidinone of formula (VIII) having a suitable protecting group P in the 1-position is condensed with the appropriate arylamine (IX), e.g. by stirring and heating under reflux the reaction components while azeotropically removing water in a suitable organic solvent, preferably an aromatic hydrocarbon, such as benzene, methylbenzene or dimethylbenzene, in the presence of a suitable acid such as, for example, 4-methylbenzenesulfonic acid, acetic acid, hydrochloric acid or the like. The resulting Schiff base (X) is then reduced with a suitable reducing agent such as e.g. sodium borohydride or catalytic hydrogenation using e.g. a platinum oxide catalyst to give the corresponding N-aryl-4-piperidinamine (II-a).

7 61482

The reactions described above are illustrated by the following reaction scheme: P-N ^ = Q + H £ N-Ar-—> O N-Ar (VIII) (IX) (X)

NaBH. , TT.

_ 4> (H-a)

Intermediates of formula (VII) wherein X is hydrogen (VII-a) are conveniently prepared starting from compound (II-a) by first deprotecting P in a conventional manner to give N-aryl-4-piperidinamine (XI) and then coupling The L substituent in the same manner as described above for the preparation of the compound (Ib) starting from the compound (Ia).

When L "* · in intermediate (VII-a) represents a methyl group, (VII-a-1), it is obtained directly by reducing intermediate (II-a) in which P is a lower alkyloxycarbonyl group, (II-a-2), with a suitable reducing agent such as lithium aluminum hydride The following reaction scheme describes the reactions described above: QI * T 2.

Connecting L L1 V

NH \ _ / IjJH

Ar Ar (XI) (VII-a)

(lower alkyl) -o-α-N V LiAlH 2 O 2 CH.-N V

v _ / ^ h: * 3 NH

Ar Ar (II-a-2) (VII-a-1) e 61482

Intermediates of formula (II) wherein X is lower, -alkyloxycarbonyl, (ΙΙ-b), can be prepared as follows.

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. and coupling of the amine group at the 4-position of the piperidine ring provides an intermediate of formula (XIII).

The nitrile (XIII) is then converted to the amide (XIV) by acid hydrolysis. Preferably, a concentrated acid can be used for this purpose, such as hydrochloric acid, phosphoric acid and preferably sulfuric acid. The amide (XIV) is then hydrolysed to the corresponding carboxylic acid (XV) using known hydrolysis to convert the amide to the acid, e.g. by treating compound (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 carboxylic acid (XV) thus obtained is in turn converted into its metal salt, preferably the sodium salt (XVI), by reaction with an alkali, e.g. sodium hydroxide. The carboxylic acid (XV) need not be isolated or purified, but may be used as a crude mixture in the preparation of compound (XVI), or the salt may be obtained directly by carrying out alkaline hydrolysis.

The salt (XVI) is then converted to the desired ester (II-b) wherein P is phenylmethyl, (II-b-1) by reaction with a suitable halogen-lower alkane (XVII) in a suitable solvent such as hexamethylphosphoric acid triamide.

Alternatively, esters (II-b-1) may be prepared by converting an acid (XV) to an acyl halide (XVIII) in a conventional manner by treatment with a suitable halogenating agent, e.g. sulfinyl chloride and reacting said acyl halide with a suitable lower alkanol, or simply reacting the acid with a suitable alcohol. acid.

The reactions described above are illustrated in the following reaction scheme: 9,61482

QcH2-Q = O + (IX) + KCN CH3COOH ^ (XII) OCH N nitrile hydrolysis to amide 2 \ 'NH>

At (XIII)

O

U

Hydrolysis of Qr.H's amide to the acid CH 2 "NH '

Ar (XIV) 0

0-OC

NaOH / Ar \ SOC1- / <xv) \ 0'-o! R "'“ * cHoir

Jlx H + Ar (XVI) - / (XVIII) - / / lower alkanol halo-lower-alkane / (/ (XVII)) (O-O (C3-)

Ar (II-b1) 61482 ίο Intermediates (II-b) in which P is lower alkyloxycarbonyl or phenylmethoxycarbonyl, (II-b-2) are easily derived from compound (II-b-1) by removal of the protecting phenylmethyl group and Senja] -ke by adding a lower alkyloxycarbonyl or phenylmethoxycarbonyl group to the compound (XIX) thus obtained in a manner known per se, e.g. by reacting compound (XIX) with a suitable lower alkyl or phenylmethylcarbonyl halide, or reacting compound (II-b-1) directly with a lower alkyl or phenylmethylcarbonyl halide, wherein the phenylmethyl group of the compound (II-b-1) is replaced by the desired lower alkyloxycarbonyl or phenylmethoxycarbonyl group.

O

Q | j - O - (lower alkyl li)

NH

Ar carbonyl halideN. (XIX) n. Carbonyl halide (II-b-2) Intermediates (VII) in which X is lower alkyloxycarbonyl, (VII-b) are prepared by attaching an L 1 group to intermediate (XIX) as described above.

Intermediates (II) and (VII) wherein X is lower alkyloxymethyl, (II-c) and (VII-c), respectively, can be prepared as follows.

The lower alkyl ester of formula (II-b) is reduced with a suitable reducing agent such as sodium dihydro-bis (2-methoxyethoxy) aluminate (Red-Al) in a suitable organic solvent such as benzene or lithium borohydride with α-piperidine. to obtain methanol (XX).

Compound (XX) is then subjected to an O-alkylation reaction with a suitable alkylating agent. The O-alkylation step can be performed by reacting compound (XX) with the appropriate halogen-lower alkane xi.

61482 or with di- (lower alkyl) sulfate in a suitable organic solvent such as benzene, methylbenzene, dimethylbenzene, tetrahydrofuran or the like with a suitable quaternary ammonium salt such as N, NN-triethylbenzenemethanamine in the presence of halide, -c). Intermediates (VII-c) can be prepared by first deprotecting compound (II-c) and then attaching an L 2 substituent to the thus obtained intermediate (XXI) as described above.

On the other hand, intermediates (VII-c) can be prepared by reducing the alkyl ester of formula (VII-b) to the corresponding 4-piperidinemethanol (XXII) in the same manner as described above for the preparation of compound (XX) starting from compound (ΙΙ-b), and then subjecting compound (XXII) to an O-alkylation reaction with a suitable lower alkyl alkylating agent according to the method described for the preparation of compound (II-c) starting from compound (XX).

The above methods are illustrated by the following reaction scheme:

O

/ - \ M.O. (lower-alkyl) Bea.A1 / ΗκΗ ->

Ar Ar (H-b) <XX> QCHo-O-i-lower alkyl)

NH

Ar (II-c) 12 61 482 aCH (lower alkyl) 1

Connecting i-T

NH

Ar (XXI) / -v CH θ (lower alkyl)

L-N V

\ _ / ^ Nh

Ar (VII-c)

O

OC-O (lower alkyl) & / - CH OH

R ed-Al γ 1 \ / 2

KH - »" ‘IJnH

Ar Ar (VH-b) <XXII> G-alkylation (VII-c) 13 61 4 82

The compounds of formula (I) and their pharmaceutically acceptable acid addition salts have excellent antiarrhythmic activity and are useful for normalizing pulse irregularity.

The antiarrhythmic activity of the compounds of the invention is described by the following experiment in dogs. The experiment was performed under stress-triggering conditions By shoreing 1 ml / 10 kg body weight of fentanyl (0.4 mg / ml) and droperidol (20 mg / mlL?).

Test compounds were administered intravenously after a test period of 30 minutes and the following evaluation principles were used: 0: no effect +: decrease in the number of premature pulses and an increase in the number of normal pulses by at least 30% compared to the control value.

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

+++: normalization of the pulse or decrease in the number of premature pulses and increase in the number of normal pulses by at least 75% compared to the control value.

The results obtained from the experiments are shown in the following tables. The compounds used have been selected to describe the useful antiarrhythmic properties of all compounds of formula (I).

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

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 volume of 4-methylbenzenesulfonic acid is stirred and refluxed for 5 hours. (Reflux condenser 11a equipped with reaction vessel and water separator). After the calculated amount of water has separated, the solvent is evaporated. The oily residue is dissolved in 800 parts of 2,2'-oxybispropane and re-evaporated to give 27 parts of N- [1- (phenylmethyl) -N-piperidinylidene] -3-pyridinamine as a yellow-brown oil.

To a stirred solution of 27 parts of N, N- (phenylmethyl) -4-piperidinylidene-3-pyridinamine in 40 parts of ethanol is added portionwise 3.8 parts of sodium borohydride. At the end of the addition, heat to 50 ° C and evaporate the solvent. The oily residue is dissolved in 150 parts of 1N hydrochloric acid and filtered.

The filtrate is made alkaline with ammonium hydroxide and extracted with methylbenzene. The organic layer is dried over magnesium sulfate, filtered and evaporated. The solid residue is washed with 2,21-oxybispropane and dried to give 14 parts of N- [1- (phenylmethyl) -4-piperidinyl] -3-pyridinamine; mp. 131-133 ° C; yellow amorphous powder.

A mixture of 20 parts of N- [1- (phenylmethyl) -4-piperidinyl] -3-pyridinamine, 160 parts of methanol, 30 parts of water and 12 parts of concentrated hydrochloric acid solution is hydrogenated under normal pressure and at a temperature of 22 to 39 ° C in the presence of is 7 parts of palladium on carbon (10%). After the calculated amount of hydrogen has elapsed, the hydrogenation is stopped. The catalyst is filtered off and the filtrate is evaporated. The oily residue is dissolved 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'-oxybisethane to give 3 parts of N- (4-piperidinyl) -3-pyridinamine, m.p. 127-12S ° C.

2i 614 82

'Example II

A mixture of 171.2 parts of ethyl H-oxo-1-piperidinecarboxylate, 159.5 parts of 4-chlorobenzeneamine, 1520 parts of anhydrous methylbenzene and a few crystals of 4-methylbenzenesulfonic acid is stirred and refluxed for 7 hours. (The reactor is equipped with a reflux condenser and a water separator). The methyl benzene is evaporated and the oily residue is triturated in vacuo to give 192 parts of oily ethyl 44-chlorophenyl (i) irninq / -1-piperidine carboxylate, b.p. 171-176 ° C at pressure f), 4 mm.

Example III

By repeating the procedure of Example II and using an equivalent amount of arylamine instead of 4-chlorobenzeneamine, the following compounds are obtained:

O

H / - \ CH3-CH2-O-C-N V = N-Ar ^ Kp. at the stated pressure 2-Cl-C6H4 160-165 ° C / 0.5-0.6 mm.

2,6- (CH3) 2-C6H3 142-145 ° C / 0.01 m.p.

2-Cl, 6-CH3-C6H3 195-200 ° C / 0.2 mm.

4-F-c6h4 145-147 ° C / 0.01 mm.

3.4- (Cl) 2-C6H3 190-200eC / 0.02-0.03 mm.

3- Cl-C6H4 165-170 ° C / 0.01-0.02 mm.

4- Br "C6H4 180-183 ° C / 0.1 mm.

2.5- (Cl) 2-C6H3 2-pyridinyl 22 61 482

Example IV

A mixture of 171 parts of ethyl 4-oxo-1-piperidinecarboxylate, 162 parts of 2,6-dichlorobenzeneamine and 800 parts of d.-methylbenzene and 1 part of 4-methylbenzenesulfonic acid is heated under stirring and heated under reflux using a water separator. . The reaction mixture is evaporated to give 260 parts of ethyl N- (2,6-dichlorophenyl) -N- (1-piperidinecarboxylate) as a residue.

Example V

A mixture of 34 parts of ethyl 4-oxo-1-piperidinecarboxylate, 20 parts of 2-pyridinamine, 8 drops of acetic acid and 90 parts of methylbenzene is stirred and refluxed for 23 hours using a water separator. The reaction mixture is evaporated to give (50 parts of ethyl 4- (2-pyrimidinylimino) -1-piperidinecarboxylate as a residue.

Example VI

To a warm solution of 192 parts of ethyl 4- (4- (4-chloro-phenyl) -imino] -1-piperidinecarboxylate in 560 parts of methanol is added portionwise 23.5 parts of sodium borohydride at 50 ° C over one hour. After the addition is complete, the mixture is stirred at the same temperature for 2 hours. The methanol is evaporated. The solid residue is heated with 600 parts of water and the product is extracted with benzene. The extract is dried over magnesium sulfate and evaporated. The oily residue solidifies on treatment with 2,2,2-oxybispropane. The material is filtered off and dried, yielding 122 parts of ethyl 4- [1- (4-chlorophenyl) -α] -nino-1-piperidinecarboxylate, m.p. 115-118 ° C.

Example VII

Following the procedure of Example VI and using an equivalent amount of ethyl 4-arylimino-1-piperidinecarboxylate, the following compounds are obtained:: 23 61 482

o H

CH, -CH, -O-li-N V

3 2 \ _ / 'nh

Ar

Ar Sp./kp.

2-Cl-C6H4 m.p. 89-93 ° C

2-C16-CH3-C6H3 m.p. 99.5eC

4-F-C / H m.p. 40-142 ° C / 0.01 mm.

6 4

3.4- (Cl) 2-C6H3 m.p. 113. 5 ° C

3- C1-C, H. sp. 72 ° C

6 4

4- Br-C, H. mp. 116.5'C

6 4

2.5- (Cl) 2-C6H3 m.p. 107.2 to 110. 3EC

m

Example VIII

To a stirred and refluxed mixture of 250 parts of ethyl 4 - [(2,6-dichlorophenyl) imino] -1-piperidinecarboxylate in 160 parts of methanol and 160 parts of 2-propanol are added portionwise 30 parts of sodium borohydride. At the end of the addition, stirring is continued for 1 hour under reflux. The warm 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 to give 96 parts of 4-2,6-dichlorophenyl) amino) -1-piperidinecarboxylate, m.p. 107.2 to 116.6 ° C.

Example XX

A mixture of 45 parts of ethyl 4- (2,6-dimethylphenyl) imino-1-piperidinecarboxylate and 0.3 part of platinum dioxide in 160 parts of methanol is hydrogenated at atmospheric pressure and at a temperature of 24-35 ° C. After the calculated amount of hydrogen has elapsed, the hydrogenation is stopped. The catalyst is filtered off and the filtrate is evaporated, the oily residue is distilled to give 30 parts of oily ethyl 4,4,4,6482 (X 2,6-dimethylphenyl) amino-7-piperidinecarboxylate as the free base, b.p. 148-153 ° C at a pressure of 0.01 mm. The hydrochloride salt is prepared from the distillate in a conventional manner in 1,1'-oxybisethane. The precipitated solid salt is filtered off and dried, yielding 28.5 parts of ethyl 4 - [(2,6-dimethylphenyl) amino] -1-piperidinecarboxylate hydrochloride, m.p. 195.5 ° C.

A mixture of 10 parts of ethyl 4- (2,6-dimethylphenyl) -amino-1-piperidinecarboxylate and 13 parts of hydrobromic acid solution (48%) is stirred at 80-110 ° C until gaseous the formation of carbon dioxide ceases (about 1 hour). The red reaction mixture is evaporated in vacuo. The residue is taken up in 56 parts of methylbenzene and the latter is evaporated again. It is then re-evaporated in a mixture of 24 parts of 2-propanone and 40 parts of methylbenzene. The resulting semi-solid residue is mixed with 80 parts of hot 2-propanone and a solid precipitates on cooling. It is filtered, washed successively with small amounts of absolute ethanol and 2-propanone and dried to give 13 parts of N- (2,6-dimethylphenyl) -4-piperidinamine dihydrobromide, m.p. + 300 ° C.

Example X

To a stirred and cooled (ice bath) mixture of 165 parts of ethyl 4- (2-pyridinylimino) -1-piperidinecarboxylate and 376 parts of methanol is added portionwise 29.5 parts of sodium borohydride (exothermic reaction). After the addition is complete, stirring is continued for 1 hour 30 minutes at room temperature. The reaction mixture is evaporated. The residue is suspended in 460 parts of water and the suspension is acidified with concentrated hydrochloric acid solution. It is made alkaline with ammonium hydroxide and the product is extracted with methylbenzene. The product is dried, filtered and evaporated. The residue is converted into the ethanedioate salt in 2-propanol and 2,2'-oxybis-propane. The salt is filtered, washed with 2,2'-oxybispropane and dried in vacuo to give 38 parts of ethyl 4- (2-pyridinylamino) -1-piperidinecarboxylate ethanedioate.

A mixture of 90 parts of ethyl 4- (2-pyridinylamino) -1-piperidinecarboxylate, 90 parts of potassium hydroxide and 720 parts of 2-propanol is stirred and refluxed for 2 days. The reaction mixture is evaporated. Add 1000 parts of water to the residue and extract the product with dichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from 2,21-oxybispropane to give 13 parts of N- (4-piperidinyl) -2-pyridinamine.

Example XI

A mixture of 7 parts of ethyl 4- (2-pyridimidinylamino) -1-piperidinecarboxylate and 120 parts of hydrobromic acid solution (48%) is stirred and refluxed for 2 hours. The reaction mixture is evaporated and the residue is taken up in water. It is then 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 in 2,2'-oxybispropane. The product is filtered and converted into the hydrochloride disalt in 2-propanol. The salt is filtered and crystallized from ethanol to give 2 parts of N- (4-piperidinyl) -2-pyrimidineamine dihydrochloride hemihydrate, m.p. 268.5 ° C.

Example XII

A mixture of 32.5 parts of methyl 4- (phenylamino) -1- (phenylmethyl) -4-piperidinecarboxylate and 200 parts of methanol is hydrogenated under normal pressure at room temperature using 5 parts of palladium on carbon (10%). After the calculated amount of hydrogen has been consumed, the catalyst is filtered off and the filtrate is evaporated, the oily residue solidifies on stirring with 2,2 * -oxybispropane. The product is filtered and dried in vacuo to give 20 parts (85%) of methyl 4- (phenylamino) -4-piperidinecarboxylate, m.p. 139.1 ° C.

Example XIII

To a stirred solution of 58 parts of ethyl 4- (N-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 40-70 ° C. At the end of the addition, stir and heat to reflux for 6 hours 15 minutes. The reaction mixture is cooled and filtered. The filtrate is washed successively with water, sodium hydrogen carbonate solution and water, then dried and evaporated in vacuo. The residue is crystallized from 1,1'-oxybisethane to give 47 parts of ethyl 4- [N- (4-chlorophenyl) -N- (phenylacetyl) amino] -1-piperidinecarboxylate, m.p. 108 ° C.

26 6 1482

Example XIV

Following the procedure of Example XIII using equivalent amounts of the appropriate ethyl β-arylamino-1-piperidinecarboxylates and arylacetyl chlorides in place of ethyl β- (1-chlorophenyl) amino] -1-piperidinecarboxylate and benzene acetyl chloride, the following compounds are obtained:

Il / "Λ / η o CH, -CH, -O-C-N X H, 3 2 V-yVB-CH.-Ar1 I ^

Ar

Ar Ar * Sp ·

2,6- (CH3) 2-C6H3 2-thienyl 94. 5®C

4-C 1-C / H. 2-thienyl 98.5 ° C

6 4

4-C1-C, H 4-Cl-C, H. 127.5 ° C

6 4 6 4

4-Cl-C6H4 4-CH3-C6H4 112. 5®C

2-Cl-C6H4 C6H5 123.0eC

2- C1,6-CH3-C6H3 C6H5] 14.5eC

4-F-C6H4 C6H5 82. 0eC

3.4- (Cl) -C, H C6H 115.0'C

3- CUC6H4 C, H1 92.0-C

4- Cl-C6H4 4-F-C6H4 109.0®C

4-C1-C, H. 3-CH, -C, H. 121.5®C

4-Br-C6H4 C6H5 114.5eC

4-Cl-C6H4 3-OCH3-C6H4 121.2eC

4-Cl-C6H4 2-Cl-C6H4 139.3eC

4-Cl-C6H4 3-Cl-C6H4 142. 7eC

2-C1,6-CH3-C6H3 4-Cl-C6H4 95.6 ° C

4-Cl-C6H4 2,6- (CH3) 2-C6H3 120.4®C

3.4- (Cl) 2-C6H3 4-Cl-C6H4 136.9® C

2.5- (Cl) 2-C6H3 4-Cl-C6H4 107.0®C

2.6- (Cl) 2-C6H3 4-Cl-Cl2H4 140.0®C

27 61482

Example XV

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 are added dropwise 7.7 parts of benzene acetyl chloride in 40 parts of benzene. After the addition is complete, heat to reflux and stir at reflux for 3 hours 45 minutes. The reaction mixture is cooled and filtered. The benzene phase is washed with water and then with sodium bicarbonate solution and water. After evaporation, an oily residue is obtained which solidifies on stirring from 1,1'-oxybisethanol to give 5 parts of ethyl 4- [N- (2,6-dimethylphenyl) -N- (phenylacetyl) amino] -1-piperidinecarboxylate, m.p. . 106 ° C.

Example XVI

To a stirred solution of 15 parts of ethyl 4 - [(4-chlorophenyl) amino] -1-piperidinecarboxylate, 5.4 parts of N, N-diethylethanamine and 160 parts of benzene are added dropwise 11.07 parts of 4 -methoxybenzeneacetyl chloride at 32-40 ° C. After the addition is complete, stir and heat to reflux for 3 hours. The reaction mixture is cooled and filtered. The filtrate is washed successively with water, sodium hydrogen carbonate 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 is filtered and recrystallized from a mixture of benzene and 1,1'-oxybisethane to give 3 parts of ethyl 4- (N- (4-chlorophenyl) -N- (f- (4-methoxyphenyl) acetylamino) - 1-piperidinecarboxylate, m.p. 137 ° C.

Example XVII

A mixture of 20 parts of ethyl 4- (N- (2-chlorophenyl) -N- (phenylacetylamino) -1-piperidinecarboxylate and 300 parts of hydrobromic acid solution (48%) is stirred and refluxed for 1 hour. The hydrobromic acid solution is removed in vacuo and water and sodium hydroxide solution are added successively to the residue, the free base is extracted with trichloromethane, dried and evaporated, the solid residue is washed with 1,1'-oxybisethane and dried to give 10.6 parts of N- (2-chlorophenyl). - (4-piperidinyl) benzeneacetamide, mp 135.5 ° C.

Example XVIII

Following the procedure of Example XVII and using an equivalent amount of the appropriate ethyl 4- [N-aryl-N- (arylacetyl) amino} -61482 28 1-piperidinecarboxylate ethyl 4- (N- (2-chlorophenyl) -M- (phenyl) instead of amine <17-1-piperidinecarboxylate the following compounds are obtained: πΟΗ ° 1 \ - / NC-CH - Ar I 2

By __Ar__ArJ__SP ·

2- C1,6-CH3-C6H3 C6H5 157 ° C

4-F-C6H4 C6H5 96.5 ° C

3.4- (Cl) 2-C6H3 C6H5 81 ° C

3- Cl-C6H4 C6H5 110. 5 “C

4- Cl-C6H4 4-F-C6H4 109®C

4-Cl-C6H4 3-CH3-C6H4 104.5eC

4-Br-C6H4 C6H5 121.5eC

4-Cl-C6H4 2-Cl-C6H4 72.9eC

4-Cl-C6H4 3-Cl-C6H4 64eC

2-Cl, 6-CH3-C6H3 4-Cl-C6H4 120.7eC

4-Cl-C6H4 2.6- (CH3) 2-C6H3 147.3eC

3.4- (Cl) 2-C6H3 4-Cl-C6H4 98.7 »C

2.5- (Cl) 2-C6H3 4-Cl-C6H4 ‘125.6» C

2.6- (Cl) 2-C6H3 4-Cl-C6H4 126.3eC

Example XIX

A mixture of 5 parts of ethyl 4- [N- (2,6-dimethylphenyl) -N- (phenylacetyl) amino] -1-piperidinecarboxylate in 60 parts of a 48% hydrobromic acid solution is heated until the formation of carbon dioxide ceases. Heating is continued for 15 minutes at 80-120 ° C. The reaction mixture is evaporated. The solid residue is washed successively with methylbenzene and 2-propanol and dried to give 4.1 parts of N- (2,6-dimethylphenyl) -N- (4-piperidinyl) benzeneacetamide hydrobromide, m.p. 251.5 ° C.

Example XX

A mixture of 10 parts of ethyl 4- [N- (4-chlorophenyl) -N- (phenylacetyl) amino] -1-piperidinecarboxylate and 125 parts of glacial acetic acid pre-saturated with hydrogen bromide is heated at 62 ° C for 9 hours 45 minutes: while 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 of 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 mixed with 56 parts of 1,1'-oxybisethane and the solid crude free base is filtered off. It is converted into the hydrochloride salt in a conventional manner in 1,11-oxybisethane and 2-propanone to give 4 parts of N- (4-chlorophenyl) -N- (4-piperidinyl) benzene acetamide hydrochloride, m.p. 206.5 ° C.

Es brand XXI

Following the procedure of Example XX and using an equivalent amount of the appropriate ethyl 4- [1-aryl-N- (arylacetyl) -amino] -1-piperidinecarboxylate as starting material, the following compounds are obtained: N- (2,6-dimethylphenyl) -N- ( 4-piperidinyl) -2-tiofenasetamidi; mp. 128 ° C; N- (4-chlorophenyl) -N- (4-piperidinyl) -2-tiofenasetamidi-hydro-chloride; mp. 201.5 ° C; 4-chloro-N- (4-chlorophenyl) -N- (4-piperidinyl) -4-bentseeniasetami dihydrochloride; mp. 222 ° C; and N- (4-chlorophenyl) -4-methyl-N- (4-piperidinyl) -benzeneacetamide; mp. 121 ° C.

Example XXII

To a stirred and refluxed mixture of 48 parts of 1- (1-methylethyl) -4-piperidinone, 1 part of 4-methylbenzenesulfonic acid and 540 parts of methylbenzene is added dropwise a solution of 30 parts of benzenamine in 90 parts of methylbenzene. At the end of the addition, stir and heat to reflux for 3 hours using a water separator. The reaction mixture is evaporated to give 72 parts of N- [1- (1-methylethyl) -4-piperidinylidene] benzeneamine as a residue.

30 61 482

To a stirred and heated (30-40 ° C) solution of 72 parts of N- [1- (1-methylethyl) -4-piperidinylidene] benzene amine in 480 parts of methanol is added portionwise 20 parts of sodium borohydride. After the addition is complete, stirring is continued overnight at room temperature. The reaction mixture is evaporated and the residue is dissolved in water. The solution is extracted with H-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 H-methyl-2-pentanone. The extract is washed with water, dried, filtered and evaporated. The residue is distilled (b.p. 135-1H0 ° C at 0.2 mm) and the distillate is crystallized from petroleum ether to give 21 parts of 1- (1-methylethyl) -N-phenyl-H-piperidinamine, m.p. 69.3 ° C.

Example XXIII

To a warm (HO C) solution of 12 parts of potassium hydroxide in 240 parts of 2-propanol is added in one portion 21 parts of ethyl N.

H- (N- (4-chlorophenyl) -N- (4-methoxyphenyl) acetyl, N-amino) -1-piperidinecarboxylate and 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 acidified 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 residue is dissolved in 1,1'-oxybisethane and, after crystallization, 10 parts of N- (4-chlorophenyl) -4-methoxy-N- (4-piperidinyl) benzeneacetamide are obtained, m.p. 129.5 ° C.

Example XXIV

To a stirred and warm (40 ° C) solution of 12 parts of potassium hydroxide in 200 parts of 2-propanol is added in one portion 21 parts of ethyl H- (N- (4-chlorophenyl) -N-3-methoxyphenyl) - acetyl./- amino)-1-piperidinecarboxylate and stir and heat to reflux for 17 hours. The reaction mixture is cooled, filtered and evaporated. The semi-solid residue is acidified with dilute hydrochloric acid, washed with 1,1'-oxybisethane and the aqueous acid 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 to give 7.8 parts of N- (4-chlorophenyl) -3-methoxy-N- (4-piperidinyl) benzeneacetamide, m.p. 85.7 ° C.

Example XXV

A mixture of 52 parts of 2-bromopropane, 19 parts of N- (4-piperidinyl) -3-piperidinamine, 33.3 parts of sodium carbonate, 3 parts of potassium iodide and 720 parts of 4-methyl-2-pentanone is stirred and refluxed. cooling 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 2,21-oxybispropane to give 1.5 parts of N- [1- (1-methylethyl) -1H-piperidinyl] -5-pyridinamine, m.p.

100.7 ° C.

Example XXVI

Following the procedure of Example XXV and using equivalent amounts of the appropriate bromides and 4- (arylamino) -4-X-piperidines as starting materials and carrying out the reaction in the indicated solvent, the following compounds are obtained as the free base or hydrochloride salt after treatment with hydrochloric acid:.

32 61 4 8 2

* H * H * H

• I — I i — I (—I

• o ° o C ►— <V-H t — t I-— «'» - <++ ++ + -1- + - 3 3 3 3 _3__ ου ουυ ο ,, o

oo ooo o U O

e vO. t '"- O Γ- IT) o fO

Q_ * · O »· · | · C> · co oo oo + J4 co m in co m o vO co cr 'cr ^ w m rH ^ + r ** <* -H * · + Cs) I O: 1 Ä 9 o

Η Λ1 fJ

2> r ^ 52 “to«

P + _ <: rg: rd afl atJ

a ^ g ^ ^ ^ ^ ε e -.

• doo ^^ ooo ^ «o • p ffi a WEATHER a

I <\ J tv] (Μ (M (M * M

in in rr <n a <o m a m a o o o o xooaaooaaaa ^ ^ O O O 0 an o o o o x £ - <- --- cn-- 0 ...... f

^> 1> 1>, N

\ c r · * <n J M -H .H .5 a <T) TJ X) o m in ή · η m m in · η '~' in aa ^ ^ a a a ^ J> a ου Γ? * υυυ ^ ν ο

00 CM CM

1ίώόώόόί1ώ ι m m m m ^ a a aa o o CJ _o 33 61482

Example XXVII

To a stirred solution of 15 parts of N- (4-chlorophenyl) -4-piperidinamine, 12 parts of N, N-diethylethanamine in 130 parts of benzene is added dropwise a solution of 10.3 parts of 3-bromo-1-propylene in 70 parts of benzene. . At the end of the addition, stir for first 20 hours 30 minutes at room temperature and then 40 minutes under reflux. The reaction mixture is cooled, filtered and the filtrate is evaporated. The residue is taken up in 1,1'-oxybisethane and treated with activated carbon. The latter is filtered off and the 1,1'-oxybisethane is evaporated to give 2.9 parts of N- (4-chlorophenyl) -1- (2-propenyl) -4-piperidinamine, m.p. 90 ° C.

Example XXVIII

To a warm (about 40 ° C) and stirred mixture of 5 parts of N- (2,6-dimethylphenyl) -4-piperidinamine, 5 parts of sodium carbonate and a few crystals of potassium iodide in 120 parts of benzene is added dropwise a solution of 5.1 parts of 1-iodopropane in 80 parts of benzene. At the end of the addition, stirring is continued for 40 hours under reflux. 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 to give 10.2 parts of N- (2,6-dimethylphenyl) -1-propyl-4-piperidinamine, b.p. 135 ° C at 0.2 mm.

Example XXIX

0.5 part of a solution of 2 parts of thiophene in 40 parts of ethanol is added 2 parts of cyclopentanone, 5.5 parts of N- (4-piperidinyl) -2-pyrimidinamine and 120 parts of ethanol. It is hydrogenated at normal pressure at room temperature using 2 parts of palladium on carbon (10%). After the calculated amount of hydrogen has elapsed, 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. Wash twice with dilute sodium hydroxide solution, dry, filter and evaporate. The residue is crystallized from 2,2'-oxybispropane. The product is filtered off and dried, yielding 2.3 parts of N- (1-cyclopentyl-4-piperidinyl) -2-pyrimidinamine, m.p. 118 ° C.

34 614 8 2

Example XXX

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

Example XXXI

To a stirred and refluxed suspension of 2 parts of lithium aluminum hydride in 120 parts of 1,1'-oxybisethane is added dropwise a solution of 13 parts of ethyl 4-β- (2,6-dimethylphenyl) amino] -1-piperidinecarboxylate. 40 parts of 1,1'-oxy-bisethane. After the addition is complete, stir and reflux for 20 hours. The reaction mixture is cooled to 5 ° C and 7 parts of water are added. The precipitate formed is filtered off, washed with 1,1'-oxybisethane as a filter and the filtrate is evaporated, the oily residue is distilled to give 5.8 parts of N- (2,6-dimethylphenyl) -1-methyl-4-piperidinamine; tr. 90-93 ° C at 0.003 mm. On standing, the distillate solidifies to give solid N- (2,6-dimethylphenyl) -1-methyl-4-piperidinamine, m.p. 45 ° C.

Example XXXII

To a stirred suspension of 5 parts of N- (4-chlorophenyl) -N- (4-piperidinyl) benzeneacetamide, 5 parts of sodium carbonate and a few crystals of potassium iodide in 200 parts of butanol are added dropwise 4 parts of 4-bromopropane at room temperature. At the end of the addition, stir and heat to reflux for 20 hours.

Then 4 parts of 2-bromopropane are added a second time and stirring and refluxing are continued for a further 19 hours. The reaction mixture is cooled, filtered and the filtrate is evaporated. The hydrochloride salt is prepared from the oily and free bases in a conventional manner in 1,1'-oxybisethane and 2-propanone. Precipitated 'i? *. · * · 1 35 61482 The solid salt is filtered off and crystallized from a mixture of 2-propanone and 2-propanol to give 2 parts of N- (4-chlorophenyl) -N- (1- (1-methylethyl) -U-piperidinyl) benzeneteacetamide. hydrochlorides, m.p. 2 6 3 ° C.

Example XXXIII

Following the procedure of Example XXXII using an equivalent amount of the appropriate bromide and N-aryl-N- (4-piperidinyl) -arylacetamide as starting material, the following compounds are obtained as the hydrochloride disaltate: 36 61 482 -] υ υ υ υ υ υ υ υ υ <ο ο ο ο ο ο ο ο ο * • inUinUvnUinvnvnvrivoU ιτ> * «ο · ο · ο ····· <>« GQ coimooo ^ co- ^ o —ιΟΟ · ^ υ ~ ι * Γ'σ'ίΟ ^ Ο'ϋνΟΝΓ 'Ϋ́Ν'ΰΝ ^ 1 ννμννννμννν OJ 1 »ο ί η Ν · 2 χ« ο · β

^ H rH M H ρ— * pH H pH p-H pH i — f pH pH I

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Example XXXIV

To a stirred and warm (U0 ° C) mixture of 5 parts of N- (14-chlorophenyl) -N- (i + -piperidinyl) benzeneacetamide, 5 parts of sodium carbonate, a few crystals of potassium iodide and 200 parts of n-butanol are added 3, 75 parts of bromocyclopentane and stirred and refluxed for 21 hours 30 minutes. An additional 5 parts of bromocyclopentane are then added and stirring at reflux is continued for a further 30 hours. The reaction mixture is cooled, filtered and the filtrate is evaporated. The oily residue solidifies on stirring in 1,1'-oxybisethane. The solid product is filtered and crystallized from 1,11-oxybisethane to give 1.1 parts of N-O-chlorophenyl) -N- (1-cyclopentyl-4-piperidinyl) benzeneacetamide, m.p. 139.5 ° C.

Example XXXV

Following the procedure of Example XXXIV and using equivalent amounts of the appropriate bromide and N-aryl-N- (4-piperidinyl) arylacetamide as starting material, the following compounds are obtained: L-fY 8 i 2

Ar L Ar Ar1__Sp.

(CH3) 2-CH-4-F-C6H4 ~ 103.5'C

(CH3) 2-CH-4-Cl-C6H4 4-Cl-C6H4 106.5 * C

3 9 61482 L Ar Ar * Sp.

(CH3) 2-CH-4-Br-C6H4 Cl2H 97 ° C

(CH) -CH- 4-Cl-C 1 H 2 -Cl-C 6 H 4 143.2eC

(CH3) 2-CH-4-Cl-C6H4 3-OCH3-C6H4 96.4 ° C

(CH3) 2-CH-4-Cl-C2H3-Cl-C2H6H6eC

• (CH3) 2-CH-2-Cl, 6-CH3-C6H3 4-Cl-C ^ 94.2eC

(CH3) 2-CH-4-Cl-C6H4 2,6- (CH3) 2-C6H3 126.6eC

(CH3) 2-CH- '2,5- (Cl) 2-C6H3 4-Cl-C6H4 102.5eC

(CH3) 2-CH-2,6- (Cl) 2-C6H3 4-Cl-C6H4 129 ° C

(CH3) 2-CH-2-Cl-C6H4 C6H5 87.5eC

4-Cl-C6H4 4-Cl-C6H4 133. leC

4-Cl-C6H4 2-Cl-C6H4 128.6eC

4-Cl-C6H4 3-OCH3-C6H4 157.5 eC

Q. 4-Cl-C6H4 3-CH2-C6H4 155-C

[) 4-Cl-C6H4 4-F-C6H4 143. S * C

40 61 4 8 2

Example XXXVI

To a stirred and refluxed mixture of 5 parts of N- (4-chlorophenyl) -N- (4-piperidinyl) benzeneacetamide, 5 parts of sodium hydrogencarbonate and 200 parts of benzene are added portionwise 6.7 parts of (bromomethyl) cyclopropane and stirring is continued and cooling is continued. 23 hours. The reaction mixture is cooled and filtered. The filtrate is evaporated. The semi-solid residue is dissolved in a mixture of benzene 1,1T-oxybisethane. The precipitated impurities are filtered off and the filtrate is evaporated again, the hydrochloride salt is prepared from the oily free base in a conventional manner, whereby after crystallization from the mixture of trichloromethane and 1,1'-oxybisethane 1.5 parts of N- (4-chlorophenyl) -N- cyclopropylmethyl) -4-piperidinyl] benzeneacetamide hydrochloride, m.p. 224 ° C.

Example XXXVII

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 is added portionwise 5 parts of 3-bromoacinamide. l-propene. After the addition is complete, heat at 50-60 ° C for 21 hours. The reaction mixture is cooled and filtered. The filtrate is washed successively with water, sodium hydrogen carbonate solution and water, dried over potassium carbonate and evaporated, the oily residue is converted into the hydrochloride salt in 1,1'-oxybisethane and 2-propanone to give 4 parts of N- (4-chlorophenyl) -N- [1- -propenyl) -4-piperidinyl] benzeneteacetamide hydrochloride, m.p. 225.5 ° C.

Example XXXVIII

Following the procedure of Example XXXVII using an equivalent amount of the appropriate N-aryl-N- (4-piperidinyl) -arylacetamide in place of N- (4-chlorothenyl) -N- (4-piperidinyl) -benzeneacetamide, the following compounds are prepared: N- (2 , 6-dimethyltenyl) -N - [(1- (2-propenyl) -4-piperidinyl] -2-thiopheneacetamide hydrochloride, mp 203.5 ° C, and N- (2,6-dimethylphenyl) -N - 1- (2-propenyl) -4-piperidinyl] -benzeneacetamide hydrochloride, mp 214 ° C.

t 41 61482

Example XXXIX

To a warm suspension of 5 parts of N- (4-chlorophenyl) -N- (4-piperidinyl) benzeneacetamide, 5 parts of sodium carbonate and a few crystals of potassium iodide in 200 parts of n-butanol are added 4 parts of 2-chloro-2-methylpropane at 30- 40 ° C. Stir and heat at reflux for 140 hours, during which time 35 parts of 2-chloro-2-methylpropane are added as follows: after heating for 15 hours, 4 parts of 2-chloro-2-methylpropane are added, after 8 hours 10 parts, 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 impurities are filtered off from the solution and the filtrate is re-evaporated, the oily residue is converted into the hydrochloride salt in the usual manner in 1,11-oxybisethane to give, after crystallization, 0.9 parts of N- (4-chlorophenyl) -N- (1-) dimethylethyl) -4-piperidinyl] benzene acetamide hydrochloride, m.p. 2 21 ° C.

Example XL

A mixture of 4 parts of iodoethane, 5 parts of N- (2,6-dimethylphenyl) -N- (4-piperidinyl) benzeneacetamide, 5 parts of sodium carbonate and a few crystals of potassium iodide in 200 parts of 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 1,11-oxybisethane to give 2 parts of N- (4-chloro-phenyl) -N- (1-ethyl-4-piperidinyl) -benzeneacetamide, m.p. 86.5 ° C.

Example XLI

Following the procedure of Example XL and using an equivalent amount of the appropriate N-aryl-N- (4-piperidinyl) -arylacetamide in place of N- (2,6-dimethyltenyl) -N- (4-piperidinyl) -benzeneacetamide, the following compounds are prepared: 2-chloro N- (4-chlorophenyl) -N- (l-ethyl-4-piperidinyl) benzene-acetamide hydrochloride; mp. 234.6 ° C; N- (4-chlorophenyl) -N- (l-ethyl-4-piperidinyl) -3-methylbenzene-acetamide; mp. 78.5 ° C; N- (4-chlorophenyl) -N- (l-ethyl-4-piperidinyl) -4-methyl-benzene-acetamide; mp. 50 ° C; and 61482 N- (4-chlorophenyl) -N- (1-ethyl-4-piperidinyl) -4-fluorobenzeneacetamide, m.p. 62.3 ° C.

Example XLII

To a stirred and refluxed 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 and 200 parts of butanol are added 4.7 parts of 1-iodopropane and stirred and refluxed for 22 hours. An additional 4.5 parts of 1-iodopropane are then added and stirring and refluxing are continued for 27 hours 30 minutes. The reaction mixture is cooled, filtered and the filtrate is evaporated. The semi-solid residue is dissolved in methylbenzene. The impurities are filtered off from the solution and the filtrate is evaporated again. The residue is crystallized from 1,11-oxybisethane at -10 ° C to give 0.9 parts of 4-chloro-N- (4-chlorophenyl) -N- (1-propyl-4-piperidinyl) benzeneacetamide, m.p. 118.6 ° C.

Example XLIII

To a stirred solution of 4 parts of N- (4-chlorophenyl) -N- (4-piperidinyl) benzeneacetamide and 3 parts of N, N-diethylethanamine in 200 parts of benzene is added portionwise 4 parts of 1-iodopropane and stirred and heated at reflux for 47 hours. Then 4 more parts of 1-iodopropane are added and stirring and refluxing are continued for a further 20 hours 20 minutes. The reaction mixture is cooled and filtered. The filtrate is washed with water, dried and evaporated in vacuo to give the hydrochloride salt of the oily free base in the usual manner in 1,1'-oxybisethane. The precipitated solid salt is filtered off and dried, yielding 3.5 parts of N- (4-chlorophenyl) -N- (1-propyl-4-piperidinyl) benzene acetamide hydrochloride, m.p. 233.5 ° C.

Example XLIV

Following the procedure of Example XLIII and using an equivalent amount of the appropriate iodoalkane and N-aryl-N- (4-piperidinyl) -acrylicacetamide instead of the 1-iodopropane and N- (4-chlorophenyl) -N- (4-piperidinyl) -benzeneacetamide used in that example the following compounds are obtained: 1 - 3 N- (2,6-dimethylphenyl) -N- (1-ethyl-4-piperidinyl) -2-thiophene acetamide hydrochloride; mp. 258 ° C; N- (U-chlorophenyl) -N- (l-ethyl-4-piperidinyl) -2-tiofeeniaseta-amide hydrochloride; mp. 220.5 ° C; N- (4-chlorophenyl) -N- (1-ethyl-4-piperidinyl) benzeneacetamide hydrochloride; mp. 215 ° C; 4-chloro-N- (4-chlorophenyl) -N- (1-ethyl-4-piperidinyl) -benzeneacetamide hydrochloride; mp. 224 ° C; and N- (M-chlorophenyl) -N- (1-propyl-4-piperidinyl) -2-thiophene acetamide; mp. 241 ° C.

Example XLV

A mixture of 4.5 parts of N- (1-cyclopentyl-4-piperidinyl) -2-pyrimidineamine, 3.4 parts of 3-methylbenzeneacetyl chloride, 2 parts of sodium carbonate and 180 parts of dimethylbenzene is stirred and refluxed. 17 hours.

An additional 9 parts of 3-methylbenzeneacetyl chloride are then added dropwise. After the addition is complete, 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 cooling in an ice bath. The product is extracted twice with trichloromethane. The combined extracts are dried, filtered and evaporated. The residue is converted into the ethanedioate salt in 2-propanol. The salt is filtered and crystallized twice: first from ethanol and then from methanol to give 1 part of N- (1-cyclopentyl-4-piperidinyl) -3-methyl-N- (2-pyrimidinyl) benzeneacetamide ethanedioate, m.p. 204.1 ° C.

Example XLVI

Following the procedure of Example XLV, using an equivalent amount of the appropriate N-aryl-4-piperidinamine and arylacetyl chloride as starting material, the following compounds are obtained as a base or acid addition salt after treatment with acid: 61482 1XV s \ _ / N-C-CH- -Ar1 I 2

Ar Γ "" 1 Alkaline or saline__Ar__Ar __ ^ oto__SP '

ΓΛ-3-pyridinyl C 1-4 H 2. (E) -2-butenedioxy-219 ° C

'- · aatti

ΓΛ. 3-pyridinyl 3-CH, -C, H4 (E) -2-butenedio-250.3 ° C

LV 5 b aatti

O 2-pyridinyl J 2 -Cl-CH 2 Cl 2 (COOH) 2 205.9 ° C

J 2 -2-pyridinyl 3-CH 3 -C 2 H 4 107.8 ° C

LT 1 '2-pyridinyl 4-Cl-C 1 H 2 base (19.2 ° C

1 \ 2-pyridinyl 2-thienyl base [_ / * 129.4 * c

O 2-Pyridinyl C (, H,. Base 108.8 * C

Γ) -2-pyridinyl C & H5 (COOH) ^ 223.5'C

(CH3) 2-CH-3-pyridinyl. base 129. 4eC

(CH3) 2-CH-3-pyridinyl 3-Cl-C6H4 base 117. 7eC

(CH3) 2-CH-3-pyridinyl 4-Cl-Cl2 146.6 ° C

(CH3) 2-CH-3-pyridinyl 2-thienyl base 126.7 ° C

(CH3) 2-CH-3-pyridinyl 3-CH3-C6H4 base at 100 ° C

(CH3) 2-CH-2-pyridinyl 3-Cl-C1H4 base 102.6 ° C

(CH3) 2-CH-2-pyridinyl CfcH5 base 72.1eC

(ch3) 2-ch-2-pyridinyl I 4-Cl-C 1 H 4 base 83.3 ° C

(CH3) 2-CH-2-pyridinyl 3-CH3-C6H4 (COOH) 2 190.6 ° C

(ch3) 2-ch-2-pyridinyl 2-thienyl j (COOH) 2 jl96.1 “C

(CH3) 2-CH-2-pyridinyl 4-Cl-C6H4 (COOH) 2 195.7 ° C

61482 4 5

Example XLVII

A mixture of 5 parts of methyl 1- (1-methylethyl) -4- (phenylamino) -4-piperidinecarboxylate, 24 parts of 4-chlorobenzeneacetyl chloride, 4 parts of sodium carbonate and 180 parts of dimethylbenzene is stirred and refluxed. 32 hours. The peak mixture is cooled, washed with dilute sodium hydroxide solution and extracted with dilute hydrochloric acid solution to give 3 layers. The oily and aqueous phases are combined and made initial with 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 into the ethanedioate salt in 2-propanol. The salt is filtered and crystallized from a mixture of 2-propanol and 2,2'-oxybispropane to give 5 parts (48%) of methyl 4- (N- [4-chlorophenyl) acetyl-N-phenylamino] -1- (1- methylethyl) -4-piperidinecarboxylate ethanedioate, m.p. 154.2 ° C.

Example XLVIII

Following the procedure of Example XLVII and using equivalent amounts of the appropriate 4-arylamino-4-piperidinecarboxylate and arylacetyl chloride as starting materials, the following compounds are obtained as the free base or acid addition salt after treatment with acid:

O

QH-o-r N — C-CH, ~ Ar 0 “" ”1 I Base or‘ L Ar K_ salt form__Sp._

(CH3) 2-CH- 3-CH3-C6H4 C2H5 (COOH} 2 198.4eC

iCH) -CH C H C H (E) -2-butene-168.5 ° C

^ Η3 * 2 5 2 5 dioaattx · 61482 L A? r Linas- tax su ^ f ~~

___ AN lamination I

(CH3) 2-CH-2-thienyl CZH5 (COOH) 2 156.8 ° C

(CHJ - CH-4-C1-C.H. C, H_ HCl 191.5eC

(CH3) 2-CH-3-CH3-C6H4 CH3 (COOH) 2170 ° C

(CH3) 2-CH-3-Cl-C6H5 CH3 (COOH) 2 152.2 ° C

(CH3) 2-CH-C6H5 CH3 (COOH) 2 165.5 ° C

(CH3) 2-CH-2-thienyl Ch3 (COOH) 2 173.6 ° C

ry 4-01-0 ^ 1 ^ C2H (E) -2-butenedioxy-195.6®C

r- \ ”aatti

[> C, H- C_Hr (E) -2-butenedio-203. 3eC

1- / 65 ^ 5 aate

I V 3-Cl-C, H. C0H_ (E) -2-butenedioxy-207. 8®C

L / 6 4 Z 5 aatti

ΓΥ 3-CH, -C, H. C, H_ (E) -2-butenedioxy-188 ° C

; Ly 3 6 4 2 5 aatti

i Q-C6H5 CH3 (COOH) 2 197.2®C

Q · 2-thienyl I CH 2 (COOH) 2 J66.4 * C

Q. 3-Cl-C6H4 CH3 base 94 ° C

Q- 3-CH3-C6H4 CH3 (COOH) 2189.5 ° C

Example IL

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 are added dropwise 5 parts of benzene acetyl chloride. At the end of the addition, stirring is continued overnight under reflux. The reaction mixture is cooled, washed successively with water, sodium hydrogen carbonate solution and again with water, dried, filtered and evaporated. The residue is converted into the hydrochloride salt in 2,2'-oxybispropane and 2-propanol. The resulting salt is filtered and crystallized from a mixture of 2-propanol and 2,2'-oxybispropane to give 2.5 parts of N- [1- (1-methylethyl) -4-piperidinyl] -N-phenylbenzeneacetamide hydrochloride, m.p. 184.4 ° C.

61 482

Example L

Following the procedure of Example IL and using equivalent amounts of the appropriate N-aryl-4-piperidinamine and arylacetyl chloride as starting materials, the following compounds are obtained as the base or acid addition salt after treatment with acid: L-O11-CH2-Ar '

Ar ~ A 1 Base or salt c L__Ar__Ar__njjoto__SP · (CH3) 2-CH-C6Hs 3-CH3-C6H4 HCl 173.6 (CH3) 2-CH-C6H5 3-Cl-C6H4 HCl 204.8 (~ rr ^ r-ττ r ET 2-thienyl (E) -2-butenedioxy-168. 1H-CH3;

CH3 4-Cl-C6H4 C6H5 base 115 ° C

C2H5 4-Cl-C6H4 3-OCH2-Cl2 base 90.7 °

nC3H ^ 2,6- (CH3 ^ -C ^ H3 2-thienyl (COOH) 2 153eC

1.8 61 4 82 L I Ar ÄdIqäs- tax salt- 7 j ____form__i_L__, nC3H? 2,6- (CH3) 2-C6H3 C6H5 (COOH) 2161 ° C and CH_ = CH-CH-, 4-Cl-C, H2-thienyl HCl 227, 5 ° Cj 2 2 6 4 j'Q - C6H5 4-Cl-C6H4 base 125.1 ° ^

Γ \ C, H_ 3-CH, -C, H (E) -2-butenedioxy-161.3 * C

L / 6 5 3 6 4 aate ί D-2-thienyl base 119eC j

D-C6H5 3-C1-C6 base 1 21.8 * C

^ Y. C6H5 C6H5 base 139.8 ° C and β-pyridinyl 4-Cl-CH2 base 149.9 ° C | ΓΛ-3-pyridinyl 3-Cl-Cl 2 HCl. l / 2H 2 O 236. 6 ° C;

Q-3-pyridinyl 2-thienyl-9.8-C

C6H5 4-Cl-C6H4 HCl 265.8 * 0 (uy C6H5 3-Cl-C6H4 HCl 255.4 * 0}

Example LI

A suspension of 1.25 parts of sodium amide in 56 parts of benzene is stirred under a nitrogen atmosphere and heated to 40 ° C. A solution of 6 parts of N- (4-chlorophenyl) -1- (1-methylethyl) -4-piperidinamine in 56 parts of benzene is then added dropwise. At the end of the addition, stir and heat to reflux for 16 hours 45 minutes. The mixture is cooled to 25 ° C and a mixture of 7.8 parts of 3,4-dichlorobenzene acetyl chloride in 88 parts of benzene is added. After stirring under reflux for 2 hours, the reaction mixture is cooled and 80 parts of water are added. Acidify with dilute hydrochloric acid solution. The aqueous phase is made alkaline with sodium hydroxide solution and the free base is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is dissolved in a mixture of 80 parts of 1,11-oxybisethane and 120 parts of hexane. The solution is cooled overnight at -10 ° C, the 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 residue 61482 49 is crystallized from hexane at -10 ° C to give 2.2 parts of 3,4-dichloro-N- (4-chlorophenyl) -N- [1- (1-methylethyl) -4-piperidinyl] benzeneacetamide, m.p. 101.7 ° C.

Example LII

Following the procedure of Example L1 and using equivalent amounts of the appropriate N-aryl-4-piperidinamine and arylacetyl chloride as starting materials, the following compounds are obtained as the base or acid addition salt after treatment with acid: 4-bromo-N- (4-chlorothienyl) -N-? 1-methyl-ethyl) -4-piperidinyylO-benzeneacetamide; mp. 118.1 ° C; 4-chloro-N- (2,6-dimetyylitenyyli) -N- ^ 1- (1-methylethyl) -4-phenyl-piperidin ^ -bentseeniasetamidi hydrochloride; mp. 268.2 ° C and N- (4-chlorophenyl) -4- (1-methylethyl) -N- [1- (1-methylethyl) -4-piperidinyl] benzeneacetamide; mp. 104.9 ° C.

Example LIU

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 pre-saturated with gaseous hydrogen chloride. The precipitated salt is filtered off and dried, yielding 7.5 parts of 4-chloro-N- (4-chlorophenyl) -N - (N- (1-methylethyl) -4-piperidinyl) benzeneteacetamide hydrochloride, mp 266.6 ° C .

Example LIV

From 6 parts of N- [1- (1-methylethyl) -4-piperidinyl] -N-tenyl-2-thiopheneacetamide (E) -2-butenedioate, the free base is liberated in the usual manner 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 into the ethanedioate salt in 2-propanol. The salt is filtered off and dried, yielding 3.2 parts of N- (1- (1-methylethyl) -4-piperidinyl] -N-phenyl-2-thiopheneacetamide diethanedioate, mp 167.4 ° C.

Example LV

From an aqueous solution of 2.8 parts of N- (2,6-dimethylphenyl) -N- (1-propyl-4-piperidinyl) -2-thiopheneacetamide dihydrochloride, the free base is liberated by making alkaline 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, a solid free base is precipitated. It is filtered and dried to give 1.6 parts of N- (2,6-dimethylphenyl) -N- (1-propyl-4-piperidinyl) -2-thiopheneacetamide, m.p. 62.5 ° C.

Example HVAC

3.9 parts of N- (1-cyclopentyl-4-piperidinyl) -3-methyl-N- (3-pyridinyl) benzeneacetamide (E) -2-butenedioate are prepared in the usual manner with dilute sodium hydroxide solution. After extraction with 2,2'-oxybispropane, the product is washed with water, dried, filtered and evaporated.

The residue is converted into the ethanedioate salt in ethanol. The salt is filtered and crystallized from a mixture of ethanol and 2,2'-oxybispropane to give 3 parts of N- (1-cyclopentyl-4-piperidinyl) -3-methyl-N- (3-pyridinyl) benzeneacetamide diethanedioate, m.p. 192.6 ° C.

Example LVII

A mixture of 50 parts of 4- (phenylamino) -1- (phenylmethyl) -4-piperidinecarboxamide and 600 parts of concentrated hydrochloric acid solution is heated under reflux for 16 hours. After cooling, the reaction mixture is concentrated under reduced pressure to a volume of 400 parts to form a precipitate. It is filtered, washed with water and 2-propanone and dried to give 43 parts of 4- (phenylamino) -1- (phenylmethyl) -4-piperidinecarboxylic acid dihydrochloride, m.p. 261-263 ° C (decomposes).

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 off. The residue is dissolved in water. The aqueous solution is made alkaline with ammonium hydroxide and extracted with a mixture of methylbenzene and 2,2'-oxybispropane. The combined organic mixtures are dried over magnesium sulfate, filtered and evaporated. the oily solution is dissolved in 200 parts of 2,2'-oxybispropane and gaseous hydrogen chloride is introduced into the solution. The precipitated hydrochloride is filtered, washed with 2-propanone, filtered again and dried to give 11.5 parts of ethyl 4- (phenylamino) -1- (phenylmethyl) -4-piperidinecarboxylate dihydrochloride, m.p. 212-214, 4 ° C.

51 61482

To a stirred and refluxed solution of 101.4 parts of ethyl 4- (phenylamino) -1- (phenylmethyl) -4-piperidinecarboxylate dihydrochloride in 640 parts of dry benzene is added dropwise a solution of 172 parts of sodium dihydrochloride. -bis (2-methoxylethoxy) aluminate (70% in benzene) in 160 parts of dry benzene. After the addition is complete, stirring is continued for 2 hours 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 into the hydrochloride salt in 2-propanol and 1,1'-oxybisethane. The salt is filtered, boiled in 2-propanol and, after cooling, the product is filtered. It is boiled once more in acetonitrile and the salt is filtered again after cooling. The free base is released in the usual manner.

After extraction with 1,1'-oxybisethane, it 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 are added 0.2 parts of N, N, N-triethylbenzenemethanamine chloride and 150 parts of 60% sodium hydroxide solution. After vigorous stirring, 10.9 parts of dimethyl sulfate are added dropwise at a temperature below 30 ° C. After the addition is complete, stirring is continued at room temperature for the first 2 hours 30 minutes and after the addition of a second portion of 2.6 parts of dimethyl sulfate 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 berene. The combined organic phases are washed with water, dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using trichloromethane containing 3% methanol and saturated with ammonia as eluent. The pure fractions are collected and the eluent is evaporated to give 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 under normal pressure at room temperature using 2 parts of palladium on carbon (10%). After the calculated amount of 52,61482 hydrogen has been consumed, the catalyst is filtered off and the filtrate is evaporated. The oily residue is dissolved in water, cooled and basified 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 on silica gel, eluting with a mixture of trichloromethane and methanol (90:10 by volume) saturated with gaseous ammonia. The pure fractions are collected and the eluent is 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 heated to reflux for 10.25 hours. After cooling, the N, N-diethylethanamine hydrobromide formed 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 is evaporated to give 5.7 parts (42.6%) of 4- (methoxymethyl) -1- (1-methylethyl) -N-phenyl-4-piperidinamine 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 some benzene at 25-32 ° C. After the addition is complete, stirring is continued for 1 hour at 26-32 ° C and then 3.60 hours at 38-55 ° C. After cooling, the precipitated product is filtered and converted into the hydrochloride salt in a mixture of 2-propanol and 2-propanone (5: 1 by volume). The salt is filtered and dissolved in absolute ethanol. After standing for 72 hours at room temperature, the precipitated product is filtered off, washed with a small amount of 2-propanone and dried to give 1.05 parts of N- [4- (methoxymethyl) -1- (1-methylethyl) -4-piperidinyl] -N- phenylbenzeneacetamide hydrochloride, m.p. 249.1 ° C.

53 614 82

Example LVIII

To a stirred mixture of 7.5 parts of N- (4-chlorophenyl) -1- (1-methylethyl) -4-piperidinamine and 80 parts of 4-methyl-2-pentanone are added dropwise 9 parts of 4- (2 -chloro-2-oxoryl) -phenyl] ethyl carbonate. After the addition is complete, heat to reflux and stirring is continued for 1 hour at reflux temperature. After cooling, the precipitated product is filtered off and stirred for 30 minutes in a mixture of alkaline water and trichloromethane. The layers are separated. The organic phase is dried, filtered and evaporated, the oily residue is purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 5.5 parts of (4- [2 - ((4-chlorophenyl)] [1- (1-methylethyl) -4-piperidinyl] amino) -2-oxoethyl} phenyl) ethyl carbonate. as a residue.

A mixture of 5.5 parts of (4- [2 - ((4-chlorophenyl) / 71 "(1" methylethyl) -N-piperidinyl] -amino) -2-oxoethyl] phenyl) ethyl carbonate and 50 parts of sodium hydroxide solution (10% ) is stirred for 90 minutes 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 trichloromethane. The extract is dried, filtered and evaporated, the oily residue is purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (80:20 by volume) as eluent. The pure fractions are collected and the eluent is evaporated, the oily residue is converted into the hydrochloride salt in 4-methyl-2-pentanone. The salt is filtered and dried in vacuo for 12 hours at 60 ° C to give 1.9 parts of N- (4-chlorophenyl) -4-hydroxy-N- [1- (1-methylethyl) -4-piperidinyl] benzene acetamide monohydro- chloride, m.p. 242.9 ° C.

Example LIX

A mixture of 8 parts of 2-propanone and 9.9 parts of N- (4-chlorophenyl) -N- (4-piperidinyl) -benzeneacetamide hydrochloride in 160 parts of methanol is hydrogenated under normal pressure at room temperature to 10% palladium on carbon. in the presence of a catalyst (2 parts).

When the calculated amount of hydrogen is bound, the catalyst is filtered off and the filtrate is evaporated. The residue is dissolved in a mixture of 2-propanone and 1,1'-oxybispropane and precipitated from solution as the hydrochloride salt. The salt is filtered off and dried, yielding 6.3 parts of N- (4-chlorophenyl) -N- [1- (1-methylethyl) -4-piperidinyl] -benzeneacetamide hydrochloride, m.p. 262.3 ° C.

Claims (2)

54 61482 A process for the preparation of novel therapeutically useful N-aryl-N- (4-piperidinyl) arylacetamides of formula (I): '-00. Nf 'NC-CH0-Ar I «> Ar and pharmaceutically acceptable acid addition salts thereof, wherein L is (C1-C10) -alkyl, (C1-C6) -cycloalkyl, (C1-C6) -cycloalkyl-lower-alkyl or lower alkenyl; Ar is phenyl, mono- or di-substituted phenyl, pyridinyl or 2-pyrimidinyl, wherein the substituent on said mono- or disubstituted phenyl is halogen or lower alkyl; Ar * - is phenyl, mono- or di-substituted phenyl or thienyl, wherein said mono- or di-substituted phenyl is substituted by halogen, lower alkyl, hydroxy or lower alkyloxy; and X is hydrogen, lower alkyloxycarbonyl or lower alkyloxymethyl, wherein when Ar and Ar both represent phenyl or substituted phenyl and X is hydrogen, then L is not (C 1 -C 6) -cycloalkyl, characterized in that a) the compound of formula (1-a) “CKicH 2 Ar 1 (1-a) Ar is N-alkylated in a manner known per se, preferably by reacting said compound (1-a) with a reactive ester of formula LY wherein Y is a reactive ester radical; in an inert organic solvent, preferably in the presence of a base, or b) for the preparation of a compound of formula (1-b) -CXI, N - / Vc-CH 2 Ar 1 (ib) Ar, in which formula represents (C 1 -C 10) alkyl, (C 1 -C 6) -cycloalkyl or (C 6 -C 6) -cycloalkyl-lower alkyl and the carbon atom attached to the piperidine nitrogen has at least one hydrogen atom is catalytically hydrogenated with an aldehyde or ketone corresponding to the alcohol L-OH and the formula A mixture of a compound of (1-a) in the presence of a suitable catalyst or c) the compound of formula (VII) xr-y L-NA \ (VII) Ar is acylated with the appropriate arylacetyl halide of formula (III) 0 halo-C-CH 2 -Ar 1 (III) in a suitable reaction-inert organic in a solvent, preferably in the presence of a base, and in the case where Ar1 in the final compound (1-b) is mono- or dihydroxyphenyl, a suitable protecting group is preferably added to said hydroxyl or hydroxyls in the starting compound (III), and after the final product is removed said protecting groups by alkaline hydrolysis, and d) if desired, converting the resulting compound of formula (I) or (1-b) into a pharmaceutically acceptable acid addition salt. Process for the preparation of N- (4-chlorophenyl) -β- (β- (1-methylethyl) -4-piperidinyl) -benzeneacetamide and its pharmaceutically acceptable acid addition salts according to claim 1, 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 prepared. Process for the preparation of N- (4-chlorophenyl) -58,61482 N- (1-ethyl-4-piperidinyl) benzeneacetamide and its pharmaceutically acceptable acid addition salts according to Claim 1, characterized in that N- (4-chlorophenyl) - N- (4-piperidinyl) benzeneacetamide is reacted with iodoethane and, if desired, a pharmaceutically acceptable acid addition salt of the product is formed. Process for the preparation of 3-chloro-N- (1-cyclohexyl-4-piperidinyl) -N-phenylbenzeneacetamide and its pharmaceutically acceptable acid addition salts according to Claim 1, characterized in that 1-cyclohexyl-N-phenyl-4-piperidine- the amine is reacted with 3-chlorobenzeneacetyl chloride and, if desired, a pharmaceutically acceptable acid addition salt of the product is formed. 57 61402 A process for the preparation of a therapeutically active compound N-aryl-N- (4-piperidinyl) arylacetamide with a formula (I) / _ / 'NC-CH2-Ar1 (I) (C 1-6 C 1-4) -alkyl (C 5 -C 8) -cycloalkyl, (C 1 -C 6 -cycloalkyl) alkyl or alkenyl, or mono- and di-substituted phenyl, pyridinyl: or disubstituted phenyl or halogen alkyl; "*" is phenyl, mono- or di-substituent phenyl or thienyl, colors are substituents i mono- or disubstituted by phenyl or halogen, alkyl, hydroxy or alkyloxy, and alkyloxycarbonyl or alkyloxymethyl, and Ar1 is a phenyl or a substituent of phenyl and X is a substituent which is L inte (C 1 -C 6) -cycloalkyl, a derivative of N, an alkyl derivative of the formula (1-a) HOc «\ / NC- CH0-Ar - ί ^ (1-a) Ar pä ett i och för sig kändt sätt företrädesvis genom reagerande av nämnda förening (1-a) med en reaktiv Ester med form eln LY color Y is a reactive ester radical, and that the reaction is an organic solvent, for which the reaction is in the base, or (b) for the reaction to the formulation (1-b) s \ Λ II i (ib) \ / 'NC- CH, -Arx I 2 Ar