IE43802B1 - Novel-n-aryl-n-(1-l-4-piperidinyl)-arylacetamides - Google Patents

Abstract

N-Aryl-N-(4-piperidinyl)arylacetamides of the formula and their salts with acids, the substituents in the formula being defined in Claim 1, are prepared. These compounds are obtained by acylating corresponding piperidine derivatives with an arylacetyl halide. The resulting compounds can be used for the drug therapy of cardiac arrhythmias.

Description

The present invention relates to N-aryl-N-(1—X,—4— piperidinyl)-arylacetamides useful as antiarrhythmic agents and methods of preparing them.

Certain N-aryl-N-(4-piperidinyl)amides having analgesic activity have been described in the prior art. A number of these compounds are described in the following references: United States Patent No. 3,164,600? and Chemical Abstracts, 77, 34349a (1972).

Among other points of difference the antiarrhythmic compounds of this invention differ from these known compounds by the nature of the arylacetamide group attached to the 4-position of the piperidine nucleus.

The novel N-aryl-N-(l-L-4-piperidinyl)arylacetamides of the present invention may structurally be represented by the general formula: L-N N-C-CH2-Ar (I) Ar and the pharmaceutically acceptable acid addition salts thereof, wherein: .

L is a hydrogen atom, an alkyl group having from 1 to 10 carbon atoms; a cycloalkyl, cycloalkyl-lower alkyl or lower alkenyl group; Ar is a phenyl, mono- or di-substituted phenyl, pyridinyl or 2-pyrimidinyl group, wherein each substituent in the mono- and di-substituted phenyl is independently a halogen atom or a lower alkyl group; Ar1 is a phenyl, mono- or di-substituted phenyl, or thienyl group, wherein each substituent in the mono- or di- 2 4 3 8 0 2 substituted phenyl is independently a halogen atom, a lower alkyl, hydroxy or lower alkyloxy group; and X is a hydrogen atom, a lower alkyloxycarbonyl or lower alkyloxymethyl group.

In one such group of compounds I, L is other than hydrogen, X is other than lower ethyloxymethyl and Ar^ is other than hydroxy substituted phenyl.

By the term alkyl as used in the definition of L is meant straight and branched chain saturated alkyl groups having from 1 to 10 carbon atoms, such as methyl, ethyl, 1-methylethyl, propyl, 1-methylpropyl, butyl, 2methylbutyl, 1,1-dimethylethyl, pentyl, hexyl, heptyl and decyl; by the term lower alkyl as used in the definition of L and in subsequent definitions is meant straight and branched chain alkyl groups having from 1 to carbon atoms, such as methyl, ethyl, 2- methylethyl, propyl, butyl, pentyl and hexyl; by the term lower alkenyl as used herein is meant alkenyl groups having from 3 to 6 carbon atoms, such as 2-propenyl, 2-butenyl, 3-butenyl and 2-pentenyl; by the term cycloalkyl" as used herein is meant cyclic alkyl groups having from 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; and by the term halogen is meant halogens of atomic weight less than 127, i.e. fluorine, chlorine, bromine and iodine.

The compounds of formula (I) wherein Ar, Ar1 and X are as above defined and L is a hydrogen atom, (I-a),may generally be prepared starting from a piperidine derivative of formula (II), wherein Ar and X are as above defined and P is an appropriate protecting group such as phenylmethyl, lower alkyloxycarbonyl or phenylmethoxycarbonyl, by first acylating (II) with an appropriate arylacetyl halide of formula (III), preferably the chloride, and thereafter eliminating the protecting group P of the compound (IV) so-obtained, using known procedures. -ο NH I Ar II ΐ + halo-C-CH2-Ar acylation (Π) (III) •a. elimination of Ar C-CHg-Ar protecting group (IV) CH2-Ar (l-a) The acylation of (XI) with (ill) may be carried out using known N-acylating techniques, e.g. by stirring and refluxing the reactants together in a suitable reaction-inert organic Solvent, preferably in the presence of an appropriate base. Suitable solvents which may be employed include, for example, aromatic hydrocarbons suchas, benzene, methylbenzene and dimethylbenzene, and halogenated hydrocarbons such as trichloromethane. Appropriate bases include, for example, alkali metal carbonates and hydrogen carbonates, alkali metal amides such as sodium amide, and organic bases suchas pyridine and K,N-diethylethanamine.

The elimination of the protecting group P may be carried out using .generally known- techniques. When the protecting group is phenylmethyl or phenylmetboxycarbonyl it is easily removed by catalytic hydrogenation using an appropriate catalyst, e.g., palladium-on-charcoal, and when the protecting group is lower alkyl oxycarbonyl its elimination may easily be accomplished by acid or alkaline hydrolysis. Acid hydrolysis may be carried out using a -443802 strong mineral acid, e.g., hydrochloric, hydrobromic or sulfuric acid and alkaline hydrolysis is conveniently carried out using alcoholic alkali, e.g. potassium hydroxide in 2-propanol.

The compounds of formula (I-b) wherein Ar, Ar^ and X are as above defined, and L is as above defined but other than hydrogen, L being represented by iA may be prepared by introducing the appropriate iA-substituent into an appropriate compound (I-a), according to known N-alkylating procedures.

Conveniently the N-alkylation may be effected by reacting (I-a) with an appropriate reactive ester of the formula ΐΛ-Υ, (V), wherein L1 is as above defined and Y is an appropriate reactive ester radical such as halogen, or a sulfonyl radical such as methanesulfonyl or 4-methylbenzenesulfonyl. The foregoing reaction may be carried out in the usual manner, for example, by stirring and refluxing the reactants together in an appropriate reaction-inert organic solvent such as a lower alkanol, e.g. methanol, ethanol, propanol or butanol; an aromatic hydrocarbon, e.g. benzene, methylbenzene or dimethylbenzene; a ketone, e.g., 4-methyl-2-pentanone; an ether, e.g., 1,4dioxane or l,l'-oxybisethane; Ν,Ν-dimethylformamide or nitrobenzene. In order to bind the acid which is liberated during the course of the reaction an appropriate base such as sodium or potassium carbonate or hydrogen carbonate or an organic base such as Ν,Ν-diethylethanamine may be added. A small amount of an alkali metal iodide, e.g. potassium iodide, may be added to enhance the reaction rate, especially when the reactive ester (V) is a chloride or bromide.

When I? in the compounds of formula (I-b) is an alkyl, cycloalkyl or cycloalky1-lower alkyl group and when the carbon atom attached to the piperidine nitrogen has at least one hydrogen atan therecn, the introduction of L* may equally well be performed by catalytic hydrogenation of a mixture of an appropriate aldehyde or ketone corresponding to the alcohol I? -OH, and a compound of formula (I-a) in the presence of an appropriate catalyst such, .as palladiumon-charcoal. In order to improve the selectivity of the hydrogenation reaction a small amount of an appropriate catalyst poison such as thiophene may be added to the mixture.

Alternatively the caipounds of formula (I-b) may be cbtained by the reaction of L? Y with a phenylmethyl-substituted compound of formula (II-1 ) to form a quaternary piperidinium salt of formula (VI), and subsequent reductive elimination of the phenylmethyl group. The quaternization reaction may be carried out, for example, by heating the reactants together in an appropriate solvent, such as acetonitrile, and elimination of the phenylmethyl group may be performed by catalytic hydrogenation using palladium-on-charcoal catalyst. The foregoing reactions are illustrated in the following schematic representation.

(VI) -(,43802 Another method of preparing the compounds of formula (I-b) comprises acylating an appropriate N-aryl-l-L1-4-piperidinamine of formula (VII) with an appropriate arylacetyl halide of formula (III) according to well-known N-acylating techniques as described above for the preparation of (IV) starting from (II) and (III).

Ar (VII) When Ar'L in the compounds (I-b) is a substituted phenyl group having as substituents one or two hydroxyl groups, either alone, or together with other substituents, it is appropriate to protect the hydroxyl groups in the corresponding starting materials (III) with an appropriate protecting group, such as a lower alkyloxycarbonyl group, whereupon a corresponding derivative of (I-b) is obtained, the protecting group of which is easily removed by alkaline hydrolysis using, for example, dilute aqueous alkali.

The compounds of the invention may be converted to their pharmaceutically acceptable acid addition salt form by treatment with an appropriate acid, such as an inorganic acid, for example, a hydrohalic acid, r.g. hydrochloric or hydrobromic, and sulfuric acid, nitric acid or phosphoric acid; or an organic acid, for example, acetic, propanoic, 2-hydroxyacetic, 2hydroxypropanoic, 2-oxopropanoic, propanedioic, butanedioic, (Z)2-butenedioic, (E)-2-butenedioic, 2-hydroxybutanedioic, 2,3dihydroxybutanedioic, 2-hydroxyl-l,2,3-propanetricarboxylic, benzoic, 3-phenyl-2-propenoic, α-hydroxybenzeneacetic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfamic, 2-hydroxybenzoic or 4-amino-2hydroxybenzoic acid. Conversely, the salt form may be converted by treatment with alkali into the free base form. 43803 The intermediates used as starting materials in the foregoing preparations, a number of which are known compounds, may be prepared as follows.

The intermediates of formula (II) wherein X is a hydrogen atom, (Il-a), may conveniently be obtained as follows. A 4piperidinone of formula (VIII), having an appropriate protecting group P in the 1-position, is subjected to a condensation reaction with an appropriate arylamine (IX), e.g. by stirring and refluxing the reactants under azeotropic water removal in an appropriate organic solvent, preferably an aromatic hydrocarbon such as benzene, methylbenzene or dimethylbenzene in the presence of an appropriate acid such as 4-methylbenzenesulfonic acid, acetic acid or hydrochloric acid. The resulting Schiff base (X) is then reduced with an appropriate reducing agent such as sodium borohydride, or by catalytic hydrogenation using, for example, platinum oxide, catalyst, to obtain the corresponding N-ary1-4piperidinamine (Il-a).

The foregoing reactions are more clearly illustrated in the following schematic representation: (VIII) (IX) (X) NaBH. —:-2_} (Il-a) The intermediates of formula (VII) wherein X is a hydrogen atom, (VH-a), may conveniently be prepared starting from (Il-a) by first eliminating the protecting group P in the usual manner to obtain an N-ary1-4-piperidinamine of formula (XI) and thereafter introducing th'-· T ^-substituent as described above for the preparation of (I-b) starting from (I-a).

When L? in the intermediates (VII-a) is a methyl group, (VII-a-1), they may directly be obtained by the reduction of an intermediate (ΙΙ-a ) wherein P is a lower alkyloxycarbonyl group, (ll-a-2), with an appropriate reducing agent such as, for example lithium aluminium hydride. The foregoing reactions are illustrated in the following schematic representation: A X/1* . introduction L -N Y NH ofL1 \_/ yH I Ar (XI) (VII-a) (lower aIkyl)-O-S-N V \_/'NH LiAlH. ___ ' \,H ch3-nJ( Ar IjJH Ar (II-a-2) (VII-a-1 ) The intermediates of formula (II) wherein X is a lower alkyloxycarbonyl group, (ΙΙ-b), may be prepared as follows.

-Phenylmethyl-4-piperidinone (XII) is reacted with an 10 appropriate arylamine (IX ) and an alkali metal cyanide, for example potassium cyanide, in an aqueous organic carboxylic acid system, such as acetic acid, or in an aqueous lower alkanol in the presence of an equivalent of an inorganic acid, sucn as hydrochloric acid, whereby introduction of the nitrile function and of the amine function is effected in the 4-position of the piperidine nucleus, yielding an intermediate of formula (XIII). -943802 The nitrile (XHX) may then be converted into the amide (XIV) by acid hydrolysis. Advantageously a concentrated strong, aqueous, inorganic acid may he used, such as hydrochloric acid, phosphoric acid and, preferably, sulfuric acid. The amide (XIV) may then be .further hydrolyzed to ctotain the corresponding carboxylic acid (XV) , by the application of known amide-to-acid hydrolysis procedures, for example by treating (XIV ) with a diluted strong acid, e. g., hydrochloric or sulfuric acid, or by alkaline hydrolysis using an appropriate base, e.g. sodium or potassium hydroxide. The carboxylie acid (XV) socbtained may then be converted into a metal salt thereof, preferably the sodium salt (XVI), by the reaction with alkali, e.g., with sodium hydroxide. The carboxylic acid (XV) need not necessarily be isolated or purified, but may be utilized as a crude mixture in the preparation of (XVI) , or the salt may be obtained directly when alkaline hydrolysis is carried out.

The salt (XVI) .may then be converted into the desired ester (Il-b) wherein P stands for phenylmethyl (II-b-1) by the reaction with an appropriate halo-lowe.r alkane (XVII) in an appropriate solvent such -is hexamethylphosphoric triamide.

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

The foregoing reactions are more clearly illustrated in the following schematic representation: O + (IX) I- KCN (XII) ch3cooh water -1043803 nitrile-to-amide hydrolysis (ΧΙΠ) I Ar o-otr I Ar amide-to-acid hydrolysis (XIV) II n>cH2£/-°H (xv) NH Ir 5OCL· lower OCH2OC'C1 alkanol \=/ \_/XNH H+ Ar (XVIII) 'lower alkanol II az—\ C-O-(lower alkyl) ch*h (II-b-1) -114 3 8 0 2 The intermediates of formula (Il-b) wherein P is a lower alkyloxycarbonyl or phenylmethoxycarbonyl group (II-b-2) are easily derived from (II-b-1) by eliminating the protecting phenylmethyl group and thereafter introducing into the so-obtained compound of formula (XIX) a lower alkyloxycarbonyl or phenylmethoxycarbonyl group according to known procedures, e.g., by the reaction of (XIX) with an appropriate lower alkyl or phenylmethyl carbonohalidate, or directly by the reaction of (II-b-1) with a lower alkyl or phenylmethyl carbonohalidate, whereupon the phenylmethyl group of (II-b-1) is replaced by the desired lower alkyloxycarbonyl or phenylmethoxycarbonyl group. o ilkyloxycarbonyl group (Vll-b) are conveniently prepared by ntroducing the ϊΛ-group into an intermediate (XIX) according o the procedures described above.

The intermediates of formulae (II) and (VII) wherein X is a ower alkyloxymethyl group, (II-c) and (VII-c) respectively, ay be prepared as described below.

An appropriate lower alkyl ester of formula (Il-b) may be sduced with an appropriate reducing agent such as sodium Lhydro-bis(2-methoxyethoxy)aluminate (Red-Al) in an appropriate rganic solvent such as benzene, or with lithium borohydride to stain a 4-piperidinemethanol of formula (XX).

The compound of formula (XX) may then be subjected to an O-alkylation reaction with an appropriate alkylating agent. The O-alkylation step may be carried out by reaction of (XX)with an appropriate halo-lower al-kane or di-(lower alkyl)sulfate in an appropriate organic solvent such as benzene, methylbenzene, dimethylbenzene or tetrahydrofuran, in the presence of an appropriate quaternary ammonium salt such as Ν,Ν,Ν,-triethylbenzenemethanaminium chloride, yielding the desired intermediate (II-c). The intermediates of formula (VII-c) may be prepared by first eliminating the protecting i group of (II-c) and thereafter introducing the L -substituent into the intermediate of formula (XXI) so-obtained, according to the procedures described above.

Otherwise the intermediates of formula (VII-c) may be prepared by reducing an appropriate alkyl ester of formula (VII-b) to the corresponding 4-piperidinemethanol (XXII) in a similar manner as dee15 cribed above for the preparation of (XX) starting from (ΙΙ-b), and thereafter subjecting (XXIX) to an O-alkylation reaction with an appropriate lower alkyl alkylating agent according to the procedures described for the preparation of (II-c)starting from (XX).

The foregoing procedures are illustrated below: C-O-(lower alkyl) Red-Al Ar OO" At (Il-b) (XX) O-alkylation —--> CHj,-O-(lower alkyl) NH I Ar (II-c) -1343802 (Π-c) elimination Hjf~^CH2°(l°Wer aUtY1) introduction of ofP V—7i Ar (XXI) , /-\ CH O(lower alkyl) L-N V 4 V_/yH Ar ( VII-c) Li -£V'ol, _0/ch2oH NH I Ar (VH-b) o Ar (XXH) NH O-alkylation^ (vn_c) -1443802 The compounds of formula (I) and their pharmaceutically acceptable acid addition salts show excellent antiarrhythmic properties and as such they are useful in the normalization of irregular cardial rhythms.

The antiarrhythmic effect of the compounds of the present invention is clearly illustrated in the following experiment in dogs.

The test was carried out under neuroleptanalgesia (1 ml per 10 kg hodyweight of fentanyl (0.4 mg/ml) and droperidol (20 mg/ml) ).

About 16 hours after the ligation of the anterior descendent branch of the left coronary artery, dogs exhibit a multifocal ventricular arrhythmia.

The test compounds were given intraveneously after a control period of 30 minutes, and the following criteria wdre adopted: : no effect, + : decrease of the number of premature beats and increase of the number of normal beats by at least 30% as compared to the control value. ++ : decrease of the number of premature beats and increase of the number of normal beats by at least 50% as compared to the control value. +++ : normalisation of cardial rhythm or decrease of the number of premature beats and increase of the number of normal beats by at least 75 % as compared to the control value.

The results obtained in this experiment are given in the following tables. The compounds listed therein are not given for the purpose of limiting the invention thereto but only to exemplify the useful antiarrhythmic properties of all the compounds within the scope of formula (I). 3802 44+ + 44· -h 4+ 4* 44· 4· 4· 4· 4* 444+ -l· 444- 3 S’ bO •g 3 < k bo cl •|4 £ ιΛ < isj 44* 4444* 4· + + 4· (6 IQ k O O co rt JO S r-C r4 «Μ ♦—< *4 £ϋϋϋυυυο $ .Sstoto totototo-Q □ co rti (0 Γ7 rt 52 to If) tn tn tn ΙΠ in tn tn tn .tn tn tn to to to to to to to a to to to to \O o o \D \O o xO o sO sO *o υ υ. O ϋ o ϋ ϋ ϋ O ϋ ϋ ϋ s sD υ I 1-4 Q sT . o O I •—4 υ I sf O υ I «-4 ϋ I ’tf to to o >£> υ υ υ I ’tf to \Ο υ I r-4 ϋ I ΤΡ to* \Ο υ r r4 ϋ I φ ΰΓ χΟ ϋ »4 υ I tf to ο υ I »4 ϋ φ κ 0° I h I φ J* ic χΟ • ϋ I r4 υ * Ν tf to *0 υ I *4 Ο C0 « ϋ σ. pf » θ 2V > a ' Ίή φ 1 ΝI-1 %x ’‘i § υΝ 2 δ-δ^ δ Qs a a I I I I I I I I T I I I t- Γ4° ®. Κ t* t* t~ to to to co -1643802 4) ϋ •d «_ e s <§ k •ri •d β k k 0 <9 n *d ri ri 43 (0 k W © t h I •’F 4* 4* + 0) w M w* © ϋ I rd ϋ I N a Ό o I »d υ I + 4· + + 4+ 4+ 44· 44* 44· + 4· 4* 4· 4· 44· 4· 4· 444 444" 4· + 44* 4· 4· 4· 44· 4444· 4ri V m ri Λ ri. 43 9) (0 ri rd rd i) ϋϋ« a a 5 V w ri ri.

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The following examples are given to illustrate. but not to limit the invention thereto. Onless otherwise stated all parts therein are by weight. -2243 8 02 EXAMPLE I A mixture of 19 parts of 1 -(phenylmethyl)-4-piperidinone, 11,8 part6 of 3-pyridinamine, 120 parts of methylbenzene and a small volume of 4-methylbenzenesulfonic acid is stirred and refluxed for 5 hours. (The reaction vessel is provided with reflux-condensor and water-separator). After the calculated amount of water is separated, the solvent is evaporated. The oily residue is dissolved in 800 parts of 2,2’-oxybispropane and evaporated again, yielding 27 parts of N-/T-(phenylmethyl)-4-piperidinylidene7-3-pyridinamine as a yellow-brown oil.

To a stirred solution of 27 parts of N-^-(phenylmethyl)-4piperidinylidene7-3-pyridinamine in 40 parte of ethanol are added portionwise 3.8 parts of sodium borohydride. After the addition is complete, the whole is heated to 50"C. The solvent is evaporated.

The oily residue is dissolved in 150 parts of hydrochloric acid IN and filtered. The filtrate is rendered 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, 2'-oxybispropane and dried, yielding 14 parts of N-/l-(phenylmethyl)-4-piperidinyl7-3-pyridinamine;' mp, 131-133*C; beige, amorphous powder.

A mixture of 20 parts of N-^(phenylmethyl)-4-piperidiny]J7_3_ pyridinamine, 160 parts of methanol, 30 parts of water and 12 parts of a concentrated hydrochloric acid solution is hydrogenated at normal pressure and at a temperature between 22-39*C, in the presence of 7'parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, hydrogenation is stopped. The catalyst is filtered off and the filtrate is evaporated. The oily residue is dissolved in water. This solution is rendered alkaline with ammonium hydroxide, saturated with solid potassium carbonate and then extracted with methylbenzene. The extract is dried over potassium -2343802 carbonate and evaporated. The solid residue is recrystallized from a mixture of 40 parts of benzene and 32 parts of 1,1'-oxybisethane, yielding 3 parts.of N-(4-piperidinyl)-3-pyridinamine; mp, 127-129°C, EXAMPLE II A mixture of 171.2 parts of ethyl 4-oxo-l-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 provided’ with a reflux-condensor and water-separator). The methylbenzene is evaporated and the oily residue is distilled in vacuo, yielding 192 parts of oily ethyl 4-/[4-chlorophenyl)imino7-l-piperidinecarboxylate; bp. 171-176’C at 0,4 mm. pressure.

EXAMPLE III By repeating the procedure of Example II and using an equivalent amount of an appropriate arylamine in place of the 4-chlorobenzenamine used therein, the following compounds are obtained: ί CH3-CH2-O-C-N =N-Ar Ar bp, at indicated pressure 2-Cl-C6H4 2,6-(CH3)2-C6H3 2-Cl, 6-CH3-C6H3 l60-l65°C /0.5-0.6 mm. 142-145‘C / 0.01 mm. 195-200’C /0.2 mm. -2443802 Ar bp, at indicated pressure 5 4-F-C6H4 3,4-(Cl)2-C6H3 3- Cl-C6H4 4- Br-C6H4 145-147’C /0.01 mm. 190-200’C / 0.02-0.03 mm. 165-170’C I 0.01-0.02 mm. 180-183’C /0.1 mm. 2,5-(Cl)2-C6H3 - 2-pyridinyl EXAMPLE IV A mixture of 171 parts of ethyl 4-oxo-l-piperidine10 carboxylate, 162 parts of 2, 6-dichlorobenzenamine,. 800 parts of dimethylbenzene and 1 part of 4-methylbenzenesulfonic acid is stirred and refluxed with water-separator. The reaction mixture is evaporated, yielding 250 parts of ethyl 4-/(2, 6-dichlorophenyl)imino7-l-piperidinecarboxylate as a residue.

EXAMPLE V A mixture of 34 parts of ethyl 4-oxo-l-piperidinecarboxylate, 20 parts of 2-pyrimidinamine, 8 drops of acetic acid and 90 parts of methylbenzene is stirred and refluxed for 28 hours with waterseparator, The reaction mixture is evaporated, yielding 50 parts of ethyl 4-{2-pyrimidinylimino)-l -piperidinecarboxylate as a residue. -25EXAMPLE VI To a warm solution of 192 parts of ethyl 4-/[4-chlorophenyl)imino7-l-piperidinecarboxylat«in 560 parts of methanol is added portionwise 23.5 parts of sodium borohydride at 50°C and over a period of 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 treating with 2,2'-oxybispropane. The solid is filtered off and dried, yielding 122 parts of ethyl 4-/[4-chlorophenyl)amino7-l-piperidinecarboxylate; mp. 115-118’C, EXAMPLE VII Following the procedure of Example VI and using an equivalent amount of an appropriate ethyl 4-arylimino-lpiperidinecarboxylate, the following compounds are prepared: Ar mp. / bp. 2-Cl-C6H4 ' mp, 89-93‘C 2-Ci; 6-CH3-G6H3 mp. 99.5’C 4-F-C6H4 bp. 140-142®C /0.01 mm. 3,4-(Cl)2-C6H3 mp. H3.5eC 3-Cl-C6H4 mp. 72°C 4-Br-C6H4 mp. 116.5-C 2,5-(Cl)2-C6H3 mp. 107.2-110.3®C 2-pyrimidinyl - EXAMPLE VIII To a stirred and refluxing mixture of 250 parts of ethyl 4-/(2, 6»dichlorophenyl)imino7-l-piperidinecarboxylate in 160 parts of methanol and 160 parts of 2-propanol are added portionwise 30 parts of sodium borohydride. Upon completion, stirring at reflux temperature is continued for one hour. The warm reaction mixture is poured onto 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 petroleumether, yielding 96 parts of ethyl 4-/(2,6-dichlorophenyl)aminq7-l-piperidinecarboxylate; mp. 107,2-116.6’C, · EXAMPLE IX A mixture of 45 parts of ethyl 4-/(2, 6-dimethylphenyl)imino7-l -piperidinecarboxylate, 0.3 parts of platinum dioxide in 160 parts of methanol is hydrogenated at normal pressure and at a temperature between 24’ and 35°C. After the calculated amount of hydrogen is taken up, hydrogenation is stopped. The catalyst is filtered off and the filtrate is evaporated. The oily residue is distilled, to yield 30 parts of the oily free base of ethyl 4-/(2, 620 dimethylphenyl)amino7~l-piperidinecarboxylate; bp. 148-153’C at . 0, 01 mm. pressure. From this distillate, the hydrochloride salt is prepared in the usual manner in 1,1 '-oxybisethane. The precipitated solid salt is filtered off and dried, yielding 28.5 parts of ethyl 4-/(2,6-dimethylphenyl)aminq7-l -piper·'-Hnecarboxylate hydrochloride; mp. 195.5’C. -274 3 8 θ 2 A mixture of 10 parts of ethyl 4-/75, 6-dimethylphenyl)amino7~ 1-piperidinecarboxylate and 135 parts of hydrobromic acid solution 48% is stirred at a temperature between 80° and 110*Ό until the evolution of gaseous carbon dioxide is ceased (about one hour). The red-coloured reaction mixture is evaporated in vacuo. The residue is taken up in 56 parts of methylbenzene and the latter is evaporated again. Then 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 on cooling, the solid product is precipitated. It is filtered off, washed successively with, small amounts of absolute ethanol and 2-propanone and dried, yielding 13 parts of N-(2,6-dimethylphenyl)-4-piperidinamine dihydrobromide; mp. + 300°C.

EXAMPLE X To-a stirred and cooled (ice-bath) mixture of 165 parts of ethyl 4-(2-pyridinylimino)-l-piperidinecarboxylate and 736 parts of methanol are added portionwise 29.5 parts of sodium borohydride (exothermic reaction). Upon completion, stirring is continued for lh, 30 at room temperature. The reaction mixture is evaporated. The residue is suspended in 460 parts of water and the suspension is acidified with a concentrated hydrochloric acid solution. The whole is alkalized with ammonium hydroxide and the product is extracted with methylbenzene. The extract is dried, filtered and evaporated. The residue is converted into the ethanedioate salt in 2-propanol and 2, 2'-oxybispropane. The salt is filtered off, washed with 2,2'-oxybispropane and dried in vacuo., yielding 38 parts of ethyl 4-(2-pyridinylamino)-l-piperidinecarboxylate ethanedioate. -2843803 A mixture of 90 parts of ethyl 4-(2-pyridinylamino)-lpiperidinecarboxylate, 90 parts of potassium hydroxide and 720 parts of 2-propanol is stirred and refluxed for 2 days. The reaction mixture is evaporated. 1000 Parts of water are added to the residue and the product is extracted with dichloromethane.

The extract is dried, filtered and evaporated. The residue is crystallized from 2, 2’-oxybispropane, yielding 13 parts of N-(4-piperidinyl)-2-pyridinamine.

EXAMPLE XI A mixture of 7 parts of ethyl 4-(2-pyrimidinylamino)1-piperidinecarboxylate and 120 parts of hydrohromic acid solution 48% is stirred and refluxed for 2 hours. The reaction mixture is evaporated and the residue is taken up in water. The whole is alkalized with a diluted 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 off and converted into the hydrochloride salt in 2-propanol, The salt is filtered off and crystallized from ethanol, yielding 2 parts of N-(4-piperidinyl)-2-pyrimidinamine dihydrochloride hemihydrate; mp. 268.5 *C, EXAMPLE XII A mixture of 32,5 parts of methyl 4-(phenylamino)-l(phenylmethyl)-4-piperidinecarboxylate and 200 parts of methanol is hydrogenated at normal pressure and at room temperature with parts of palladium-on-charcoal catalyst 10%, After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The oily residue solidifies on scratching in 2,2'-oxybispropane. The product is filtered off and dried in vacuo, yielding 20 parts (85%) of methyl 4-(phenylamino)-4piperidinecarboxylate; mp. 139. l’C. 2943802 EXAMPLE XIII To a stirred solution of 58 parts of ethyl 4-/4-chlorophenyl)amino7-l-piperidinecarboxylate in 240 parts of benzene is added dropwise a solution of 46,2 parts of benzeneacetyl chloride in 80 parts of benzene at a temperature between 40-70*C.

Upon completion, the whole is stirred and refluxed for 6h, 15.

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, yielding 47 parts of ethyl 4-/^-(4-chlorophenyl)-N-(phenylacetyl)aminq71-piperidinecarboxylate; mp. 108*C, EXAMPLE XIV Following the procedure of Example XIII and using equivalent amounts respectively of an appropriate ethyl 4-arylamino-1-piperidinecarboxylate and of an appropriate arylacetyl chloride in place of the ethyl 4-/(4-chlorophenyl)amino7-l-piperidinecarboxylate and benzeneacetyl chloride used therein, the following compounds are prepared: -30<»3803 Ar Ar1 mp. 2,6-(CH3)2-C6H3 2-thienyl 94.5’C 4-Cl-C6H4 2-thienyl 98.5’C 4-Cl-C6H4 4-Cl-C6H4 127.5’C 4-Cl-C6H4 4-CH3-c6H4 112.5’C 2-Cl-C6H4C6H5 123.0’C 2-C1, 6-CH3-C6H3 <=A 114.5’C 4-F-C6H4C6«5 82.0’C 3,4-(Cl)2-C6H3 V, 115.0’C 3-Cl-C6H4C6H5 92,‘0’C 4-Cl-C6H4 4-F-C6H4 109. 0’C 4-Cl-C6H4 ' 3-CH3-C6H4 121.5’C 4-Br-C6H4C6H5 114.5’C 4-Cl-C6H4 3-OCH,-CaH4 121.2’C 4-Cl-C6H4 2-Cl-C6H4 139.3’C 4-Cl-C6H4 o 4 142. 7’C 2-C1,6-CH3-C6H3 4-Cl-C,H„ 6 4 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-C&H3 4-Cl-C,H. 6» 4 140.0’C EXAMPLE XV To a stirred solution of 8 parts of ethyl 4-/j2,6-dimethylphenyl)aminq7-l-piperidinecarboxylate in 4 parts of pyridine and 80 parts of benzene are added dropwise 7. 7 parts of benzeneacetyl chloride in 40 parts of benzene. After the addition is complete, the whole is heated to reflux and stirred at reflux temperature for 3h. 45. The reaction mixture is cooled and filtered. The benzene-phase is -3143802 washed with water and then with sodium hydrogen carbonate solution'and with water. After evaporation, an oily residue is obtained, which solidifies on triturating in 1,1’-oxybisethane, to yield 5 parts of ethyl 4-/9-(2, 6-dimethylphenyl)-N-(phenylacetyl)amino71-piperidinecarboxylate; mp, 106°C.

EXAMPLE XVI To a stirred solution of 15 parts of ethyl 4-/4-chlorophenyl)amino/-! -piperidinecarboxylate, 5.4 parts of N, N-diethylethanamine and 160 parts of benzene is added dropwise 11.07 parts-of 4-methoxybenzeneacetyl chloride at a temperature between 32° to 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 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 product is filtered off and recrystallized from a mixture of benzene and 1,1 ’-oxybisethane, yielding 3 parts of ethyl 4-jN-(4-chlorophenyl)-N-^4-methoxypheny^ac etylamino 1-1 -piperidinecarboxylate; mp. 137°C, EXAMPLE XVII A mixture of 20 parts of e*hyl 4- /9-(2-chlorophenyl)-N(phenylacetyl)amino7-l -piperidinecarboxylate and'300 parts of hydrobromic acid solution 48% is stirred and refluxed for lh. 10, The hydrobromic acid solution 48% is removed in vacuo and to the residue is added successively water and sodium hydroxide solution. The free base is extracted with trichloromethane. The latter is dried and evaporated. The solid residue is washed with 1, l'-oxybis-. ethane and dried, yielding 10. 6 parts of N-(2-chlorophenyl)-N(4-piperidinyl)benzeneacetamide; mp. 135.5"C. -324380 EXAMPLE XVIII Following the procedure of Example XVII and using and equivalent amount of an appropriate ethyl 4-/N-aryl-N-(arylacetyl)aminq7-l-piperidinecarboxylate in place of the ethyl 4-/N-(2-chlorophenyl)-N-(phenylacetyl)aminq7-l-piperidihecarboxy late used therein, the following compounds are obtained: πθ(Η ft 1 \/ N-C-CHZ-Ar Ar Ar Ar1 mp. 2-CI, 6-CH,-C,HC6H5 157'C 4-F-C6H4C6H5 96.5‘C 3,4-(Cl)2-C6H3CA 81*C 3-Cl-C6H4C6H5 110.5’C 4-Cl-C6H4 4-F-C6H4 109’C 4-Cl-C6H4 3-CH3-C6H4 104.5’C 4-Br-C6H4C6H5 121.5’C 4-Cl-C6H4 2-Cl-C6H4 72.9‘C 4-Cl-C6H4 3-Cl-C6H4 64*C 2-CI, 6-CH3-C6H3 4-Cl-C6H4 120.7‘C 4-Cl-C6H4 2,6-(CH3)2-C6H3 147.3’C 3,4-(Cl)2-C6H3 4-Cl-C6H4 98. 7‘C 2.5-(Cl)2-C^H3 4-C1-C.H. 6 4 125.6‘C 2,6-(Cl)2-C6H3 4-Cl-C6H4 126.3’C EXAMPLE XIX A mixture of 5 parts of ethyl 4-/N-(2, 6-dimethylphenyl)-N(phenylacetyl)aminoT-l-piperidinecarboxylate in 60 parts ofr. hydrobromic acid solution 48% is warmed until the evolution of carbon dioxide is ceased. Heating is continued for 15 minutes at a temperature between 80"-120°C, The reaction mixture is evaporated. The solid residue is washed successively with methylbenzene and 2-propanofte and dried, yielding 4,1 parts of N-(2, 6-dimethylphenyl)N-(4-piperidinyl)benzeneacetamide hydrobromide; mp. 251,5°G, EXAMPLE XX A mixture of 10 parts of ethyl 4-^-(4-chlorophenyl)-N(phenylacetyl)amino7-l-piperidinecarboxylate and 125 parts of glacial acetic acid, previously saturated with gaseous hydrogen bromide, is heated for 9h.45 at 62°C, while stirring. The reaction mixture is cooled and glacial acetic acid is evaporated in vacuo.

The semi-solid residue is taken up in 150 parts of water, alkalized with a 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; l’-oxyhisethane and the solid crude-free base is filtered off. It is converted into the hydrp.chloride salt, in the conventional manner in 1,1 '-oxybis ethane and 2-propanone, yielding 4 parts of N-(4-chlorophenyl)-N-(4-piperidinyl)benzeneacetamide hydrochloride; mp. 206.5°C. -3443802 EXAMPLE XXI Following the procedure of Example XX and using an equivalent amount of an appropriate ethyl 4-/7(f-aryl-N-(arylacetyl)aminq7-l-piperidinecarboxylate as a starting material, the following compounds are prepared: N-(2, 6-dimethylphenyl)-N-(4-piperidinyl)-2-thiopheneacetamide; mp. 128 °C; N-(4-chlorophenyl)-N-(4-piperidinyl)-2-thiopheneacetamide hydrochloride; mp, 201,5’C; 4-chloro-N-(4-chlorophenyl)-N-(4-piperidinyl)-4-benzeneacetamide hydrochloride; mp. 222 eC; and N-(4-chlorophenyl)-4-methyl-N(4-piperidinyl)benzeneacetamide; mp. 121‘C.

EXAMPLE XXII To a stirred and refluxing mixture of 48 parts of l-(l-methylethyl)-4-piperidinone, 1 part of 4-me'thylbenzenesulfonic acid and 540 parts of methylbenzene is added dropwise a solution of 30 parts of benzenamine in 90 parts of methylbenzene. Upon completion, the whole is stirred and refluxed for 3 hours with water-separator. The reaction mixture is evaporated, yielding 72 parts of N-/l-(l-methylethyl)-4-piperidinylidene7benzenamine as a residue.

To a stirred and warmed (30-40’C) solution of 72 parts of N-/T-(l-methylethyl)-4~piperidinylidene7benzenamine in 480 parts of methanol are added portionwise 20 parts of sodium horohydride. Upon completion, stirring is continued overnight at -354380 2 at room temperature. The reaction mixture is evaporated and the residue is dissolved in water. The solution is extracted with 4methyl-2-pentanone. The extract is washed with water and acidified with a diluted hydrochloric acid solution. The aqueous acid phase is alkalized with a diluted sodium hydroxide solution till pH 9 and the product is extracted with 4-methyl-2-pen'tanone, The extract is washed with water, dried, filtered and evaporated. The residue is distilled (bp. 135-140°C at 0.2 mm, pressure) and the distillate is crystallized from petroleumether, yielding 21 parts of 1-(1methylethyl)-N-phenyl-4-piperidinamine; mp. 69.3®C.

EXAMPLE XXIII To a warm (40°C) solution of 12 parts of potassium hydroxide in 240 parts of 2-propanol are added at once 21 parts of ethyl 4-^N-(4- chlor ophenyl) -N- /f£-methoxyphenyl)ac etyl/amino J -1 -piperidine carboxylate and the whole 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 acidified with diluted hydrochloric acid solution. The acid solution is washed with I, I'-oxybisethane, alkalized with sodium hydroxide and the free base is extracted with methylbenzene. The latter is dried, filtered and evaporated. The residue is dissolved in 1,I'-oxybisethane and after crystallization, 10 parts of N-(4-chlorophenyl)-4-methoxy-N-(4piperidinyl)benzeneacetamide are obtained; mp. 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 are added at once 21 parts of ethyl 4-^N-(4~chlorophenyl)-N-/[3-methoxyphenyl)acetyl7amino J-l-piperidinecarboxylate and the whole is stirred and refluxed for 17 hours. The reaction mixture is cooled, filtered and evaporated. -3643803 The semi-solid residue is acidified with a diluted hydrochloric acid solution, washed with 1,1'-oxybisethane and the aqueous acid phase Is alkalized with sodium hydroxide solution. The free base is extracted with trichlorometh'ane. The extract is dried and evaporated. The residue is crystallized from a mixture of 1,1'-oxybisethane and hexane, yielding 7.8 parts of N-(4-chlorophenyl)-3-methoxy-N-(4piperidinyl)benzeneacetamide; mp. 85, 7"C, EXAMPLE XXV A mixture of 52 parts of 2-bromopropane, 19 parts of N-(4-piperidinyl)-3-pyridinamine, 33, 3 parts of sodium carbonate, 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'-oxybispropane, yielding 1.5 parts of N-/T-(l-methylethyl)-4-piperidinyl7-3-pyridinamine; mp. 100. 7’C.

EXAMPLE XXVI Following the procedure of Example XXV and using equivalent amounts respectively of an appropriate bromide and of an appropriate 4-(arylamino)-4-X-piperidine as starting materials and carrying out the reaction in the indicated solvent, the following compounds are obtained in free base form or in hydrochloride salt form after treatment with hydrochloric acid: -3743802 1 Solvent j f-M •OOO ί-l kH k-l kH · kM kM k-i *5 *5 h S 2 2 S S 2 2 £ %. 1 · 6 ο u υ ο ο υ r, o © Ο Ο © Ο © U © \0 Γ— U Γ~ 4* Μ4 ΙΟ© <0 • · <3 · · « | · Ο · οο co [ base ox salt form ] 1 O N w o . cq < W > 0 0 0 0 . — ω ω « w lrtrt-4 ΟΟΛΛ ϋΟΟΛΧίΟ B B - Β Β Β B M (\) N N N N K in in ffi μ < Β Ό Ο I £. ·£, .s .a .a •0 Ό Ό Γί •Η *rt ·Η in ιη £ Β in m in H 'y in ffitE fc'fc' WKB fcAB f—< f—4 Dj O,. Γ*4 Γ*’ Uj vcl •Ό *O | | Ο Ό Ό | w **0 ϋϋίΟίΜϋϋϋΜΝΟ Ιίόώόόόίίό in EXAMPLE XXVII 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 a solution of 10.3 parts of 3-bromo5 1-propene in 70 parts of benzene. Upon completion, the whole is stirred first for 20h, 30 at room temperature and further for 40 minutes at reflux. The reaction mixture is cooled, filtered and the filtrate is evaporated. The residue is taken up in 1, l’-oxybisethane and treated with activated charcoal. The latter is filtered off and. the 1,1'-oxybisethane is evaporated again, yielding 2.9 parts of N-(4chlorophenyl)-l-(2-propenyl)-4-piperidinamine; mp, 9Q°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 car15 bonate, 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. After the addition is complete, stirring is continued for 40 hours at 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, yielding 10,2 parts of N-(2, 6-dimethylphenyl)-l-propyl4-piperidinamine; bp. 135’C at 0.2 mm, pressure, EXAMPLE XXIX To 0.5 parts of a solution of 2 parts of thiophene in 40 parts of ethanol, are added 2 parts of cyclopentanone, 5,5 parts of N-(4-piperidinyl)-2-pyrimidinamine and 120 parts of methanol.

The whole is hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal 10%. After the calculated -3943802 amount of hydrogen is taken up, the catalyst is filtered off and the filtrate-is evaporated. The residue is taken up in 4-methyl-2pentanone and a small amount of trichloromethane. The whole is washed twice with a diluted sodium hydroxide solution, dried, filtered and evaporated. The residue is crystallized from 2, 2'-oxybispropane. The product is filtered off and dried, yielding 2. 3 parts of N-(lcyclopentyl-4-piperidinyl)-2-pyrimidinamines mp. 118°C.

EXAMPLE XXX To 0.5 parts of a solution of 2 parts of thiophene in 40 parts of ethanol, are added 4 parts of 2-propanone, 4.5 parts of N-(4-piperidinyl)-2-pyrimidinamine and 120 parts of methanol.

The whole is hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is dissolved in trichloromethane. The solution is washed successively with a diluted sodium hydroxide solution and with water, dried, filtered and evaporated, yielding 3 parts ofN-/L-(l-methylethyl)4-piperidinyj7-2-pyrimidinamine as a residue.

EXAMPLE XXXl To a stirred and refluxing suspension of 2 parts of lithium aluminiumhydride in 120 parts of 1,1'-oxybisethane is added dropwise a solution of 13 parts of ethyl 4-/N-(2,6-dimethylphenyl)amino7-lpiperidinecarhoxylate in 40 parts of 1,1 '-oxybisethane. After the addition is complete, stirring and refluxing is continued for 20 hours. The reaction mixture is cooled to 5°C and 7 parts of water are added. The formed precipitate is filtered off, washed on the filter with 1,1'-oxybisethane and the filtrate is evaporated. The oily residue is distilled, yielding 5. 8 parts of N-(2, 6-dimethylphenyl)-l-methyl4-piperidinamine; bp. 90-93°C at 0,003 mm. pressure. On standing the distillate solidifies, to yield solid N-(2, 6-dimethylphenyl)-lmethyl-4-piperidinamine with a melting point of 45 C. -4043803 EXAMPLE XXXII To a stirred suspension of 5. parts of N-(4-chlorophenyl)N-(4-piperidinyl)benzeneacetamide, 5 parts of sodium carbonate, a few crystals of potassium iodide in 200 parts of butanol is added dropwise 4 parts of 2-bromopropane at room temperature. After the addition is complete, the whole is stirred and refluxed for 20 hours. Then the second portion of 4 parts of 2-bromopropane is added and stirring and refluxing is continued for another 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 conventional manner in 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-/l-(l -methylethyl) 4-piperidinylTbenzeneacetamide hydrochloride; mp, 263’C.

EXAMPLE XXXIII Following the procedure of Example XXXII and using an equivalent amount of an appropriate bromide and of an appropriate N-aryl-N-(4-piperidinyl)arylacetamide as starting materials, the following compounds are prepared in hydrochloride salt forms •414380? u u ϋ ϋ • U ϋ ϋ ϋ Q o β β 0 o β. o 0 β tn o in ϋ in o in in in in k© ϋ tn • o • o • o • « • * • o a cn N o O'*· kO Tjl nJ © »«h CO 4* in r- σ* co r- kO kO k© m n- k© k© nJ N nl nJ nj nJ nJ nJ nJ nj nJ nj nj ni υουυυυυουυου ϋ ΚΒΒΒΒΒΒΒΒΒΒΒ Β tf β να Ο I . 1ft Ift Β Β Μ««ϋ ϋ Β ο ι. ,ί° 1 ϋ tf tf Β . Ό ϋ Μ Ό I Ο Ν tf J* Ε μ< •Ψ SO fc Ε U *0 *© ι η ϋ V »Λ Ε ri l./* Ε Ε &u ο ο Ε Ε \Ο \Ο · I I \Ο kO ϋ Ο 4 «η «Ψ Ο Ο «η co Ε Ε kO kO Ο Ο ι ¢0 Ε ϋ° r cn «ο Ε k© ,ϋ tf Ν nJ tf jg *J< ι Μ* Μ* Μ1, ι Ε ρί <η Ε ο Ε ν Ε Ε Ε μ Ε Ε >ο ic ic '©ι Ό *© '©CT **© υϋϋϋνόϋϋϋϋϋϋϋϋ I o <> t * ι «X- I I I «X» I I »—ι I ι 1 fM »—4 I I"4 r-H t—{ | «-Μ r4 OvOvbOOUtfQOU tfUU I ..III .111 .11 tfNNtfNtflftlft tftflfttftf B o b o ,bm u I co B ϋ I I I I I I I III I Β Β Β Β Β Β Β Β Β Β B οοϋϋυϋϋϋϋϋϋ , I I I I I I I I I I I q.

NNNNNNMNNIMMiri *-*» ***. ·» «—«. »»"»- »"» ^-«· *"*. Μ-» ΒΒΒΒΒΒΒΒΒΒΒϋ 1ft o w 4243802 u ϋ ϋ ϋ ϋ o • o 0 a in in in in 00 • • • • • in r· P" CO sO N r* in co t- M ·—1 fM w (M Μ* rΝ m mm ιη· a a a a Ό Ό Ό <0 U ϋ ϋ U J* a o O I tn a o M* tf M· + E E E a a a M3 *o vO Ό o m ϋ ϋ ϋ ϋ I υ υ· 1 fH 1 F·4 1 1 —1 r-l o o ϋ ϋ υ υ I 1 ·+ 1 xf M1 ·+ Μ* 4 N a o I M a o sf o.

B tn m n ϋ .Η X « a a © fn Sp f- —1 a o u u υ « « c όφ in -4343802 EXAMPLE XXXIV To a stirred and warm (40°C) mixture of 5 parts of .N-(4-chlorophenyI)-N-(4-piperidinyl)benzeneacetamide, 5 parts of sodium carbonate, a few crystals of potassium iodide and 200 parts of nbutanolis added 3. 75 parts of bromocyclopentane and the whole is stirred and refluxed for 21h. 30. Then a second portion of 5 parts of bromocyclopentane is added and stirring at reflux temperature is continued for another 30 hours. The reaction mixture is cooled, filtered and the filtrate is evaporated. The oily residue solidifies on triturating in 1,1 '-oxybisethane. The solid product is filtered off and crystallized from 1,1’-oxybisethane, yielding 1,1 parts of N-(4-chlorophenyl)-N-(1 -cyclopentyl -4-piperidinyl)benzeneacetamide; mp, 139.5‘C.

EXAMPLE XXXV Following the procedure of Example XXXIV and using equivalent amounts respectively of an appropriate bromide and of an appropriate N-aryl-N-(4-piperidinyl)arylac,etamide as starting materials, the following compounds are obtained: -Ar Ar L Ar Ar1 mp. (ch3)2-ch- 4-F-C6H4C6H5 108.5°C (ch3)2-ch- 4-Cl-C6H4 4-Cl-C6H4 106.5‘C -4443802 L Ar Ar1 mp. (ch3)2-ch- 4-Br-C/H, 6 4C6H5 97’C (ch3)2-ch- 4-Cl-C6H4 2-C1-C.H, 6 4 143.2®C (ch3)2-ch- 4-Cl-C6H4 3-0CH_-C,H. . 3 6 4 96.4C (ch3)2-ch. ' 4-cl-G6H4 3-Cl-C6H4 61.6’C . (ch3)2-ch- 2-C1, 6-CH3-C6H3 4-Cl-C6H4 94.2’C (ch3)2-ch- 4-Cl-C6H4 2,6-(CH3)2-C6H3 126.6’C (ch3)2-ch-· 2,5-(Cl)2-C6H3 4-Cl-C,H. 6 4 102.5’C (CH3)2-CIi- 2,6-(Cl)2-C6H3 4-Cl-C6H4 129.l’C (CH3)2-CH- 2-Cl-C6H4C6H5 87.5’C o 4-Cl-C6H4 4-C1-C.H. 6 4 133.1’C . D- 4-Cl-C6H4 2-Cl~C,H. 6 4 128.6’C 4-Cl-C6H4 3-OCH3-C6H4 157.5’C 0 4-Cl-C6H4 3-CH3-C6H4 155’C O 4-Cl-C6H4 4-F-C6H4 143,5’C -45EXAMPLE XXXVI To a stirred and refluxing mixture of 5 parts of N-(4chlorophenyl)-N-(4-piperidinyl)benzeneacetamide, 5 parts of sodium hydrogen carbonate and 200 parts of benzene are added portion-wise 6. 7 parts of (bromomethyl)cyclopropane and stirring and refluxing is continued 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 conventional manner, yielding, after crystallization of the crude salt from a mixture of trichloromethane and 1,1'-oxybisethane, 1,5 parts of N-(4-chlorophenyl)-N-/T-(cyclopropylmethyl)-4piperidinyl/benzeneacetamide hydrochloride; mp, 224®C.

EXAMPLE XXXVII To a stirred solution of 5 parts of N-(4-chlorophenyI)N-(4-piperidinyl)benzeneacetamide, 3,8 parts of N, N-diethylethanamine in 200 parts of benzene are added portion-wise 5 parts of . 3-bromo-l-propene. After the addition is complete, the whole is heated for 21 hours at a temperature between 50-60®C. 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, yielding 4 parts of N-(4-chlorophenyl)-Ν-/Ϊ(2-propenyl)-4-piperidinyl7benzeneacetamide hydrochloride; mp. 225,5°C. -4643802 EXAMPLE XXXVIII Following.the procedure of Example XXXVII and using an equivalent amount of an appropriate N-aryl-N-(4-piperidinyl)arylacetamide in place of the N-(4-chlorophenyl)-N-(4-piperidinyl)• 5 henzeneacetamide used therein, the following compounds are prepared: N-(2, 6-dimethylphenyl)-N-/T-(2-propenyl)-4-piperidinyi7-2thiopheneacetamide hydrochloride; mp. 203.5 °C; and N-(2, 6-dimethylphenyl)-N-/T-(2-propenyl)-4-piperidinyJ^benzene10 acetamide hydrochloride; mp. 214’C, EXAMPLE XXXIX To a warm suspension of 5 parts of N-(4-chlorophenyl)~ N-(4-piperidinyl)benzeneacetamide, 5 parts of sodium carbonate, a few crystals of potassium iodide in 200 parts of n, butanol is added 4 parts of 2-chloro-2-methylpropane at a temperature of 30-40’C.

The whole is stirred and refluxed for 140 hours during which time, 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 is 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 solution is filtered from some impurities and the filtrate is evaporated again. From the oily residue, the hydrochloride salt is prepared in the conventional manner in 1,1'-oxybisethane, yielding, after recrystallization of the crude solid salt from 2-propanone, 0.9 parts of N-(4-chlorophenyl)-N-/f-(l, 1-dimethylethyl) -4-piperidinyj7 henzeneacetamide hydrochloride; mp. 221 C, -4743802 EXAMPLE XL A mixture of 4 parts of iodoethane, 5 parts of N-(2, 6dimethylphenyl)-N-(4-piperidinyl)benzeneacetamide, 5 parts of sodium carbonate, 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 1,1'-oxybisethane, yielding 2 parts of N-(4-chlorophenyl)-N-(l-ethyi-4-piperidinyl)benzeneacetamide; mp. 86.5eC.

EXAMPLE XLI Following the procedure of Example XL. and using an equivalent amount of an appropriate N-aryl-N-(4-piperidinyl)arylacetamide in place of the N-(2, 6-dimethylphenyl)-N-(4piperidinyl)bettzeneacetamide used therein, the following compounds are prepared: 2-chloro-N-(4-chlorophenyl)-N-(l-ethyl-4-piperidinyl)benzeneacetamide hydrochloride; mp. 234.6°C; N-(4-chlorophenyl)-N-(l-ethyl-4-piperidinyl)-3-methylbenzeneacetamide; mp, 78.5®C; N-(4-chlorophenyl)-N-(l-ethyl-4-piperidinyl)-4imethylbenzeneacetamide; mp. 50°C; and N-(4-chlorOphenyl)-N-(l-ethyl-4-piperidinyl)-4-fl.uorobenzeneacetamide; mp. 62.3°C. -48I 438 02 EXAMPLE XLI1 To a stirred and refluxing mixture of 5 parts of 4-chloroN-(4-chlorophenyl)-N-(4-piperidinyl)benzeneacetamide, 5 parts of sodium carbonate, 0.4 parts of potassium iodide and 200 parts of butanol is added 4. 7 parts of 1 -iodopropane and the whole is stirred and refluxed for 22 hours. Then a second portion of 4.5 parts of 1-iodopropane is added and stirring and refluxing is continued for 27h. 30. The reaction mixture is cooled, filtered and the filtrate is evaporated. The semi-solid residue is dissolved in methylbenzene.

The solution is filtered from some impurities and the filtrate is evaporated again. The residue is crystallized from 1,1'-oxybisethane at -10*C, 'yielding 0.9 parts of 4-chloro-N-(4-chlorophenyl)-N(l-propyl-4-piperidinyl)benzeneacetamide; mp. 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 are added portionwise 4 parts of 1 -iodopropane and the whole is stirred and refluxed for 47 hours. Then the second portion of 4 parts of 1-iodopropane is added and stirring and refluxing is continued for another 20h. 20. 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 conventional manner in 1, l’-oxybisethane. The precipitated solid salt is filtered off and dried, yielding 3.5 parts of N-(4-chlorophenyl)-N-(l-propyl-4-piperidinyl)benzeneacetamide hydrochlorides mp. 233.5‘C. -4943803 EXAMPLE XLIV Following the procedure of Example XLIII and using an equivalent amount respectively of an appropriate iodoalkane and of an appropriate N-aryl-N-(4-plperidinyl)arylacetamide in place of the 1-iodopropane and the N-(4-chlorophenyl)-N-(4piperidinyl)benzeneacetamide used therein, the following compounds are obtained: ’ N-(2, 6-dimethylphenyl)-N-(l-ethyl-4«piperidinyl)-2-thiopheneacetamide hydrochloride; mp. 258’C; N-(4-chlorophenyl)-N-(1 - ethyl-4-piper idinyl)-2-thiopheneacetamide hydrochloride; mp, 220.5°C; N-(4-chlorophenyl)-N-(l-ethyl-4-piperidinyl)benzeneacetamide hydrochloride; mp. 215°C; 4-chloro-N-(4-chlorophenyl)-N-(I-ethyl-4-piperidinyl)benzeneacetamide hydrochloride; mp. 224’C; and N-(4-chlorophenyl)-N-(l-propyl-4-piperidinyl)-2-thiopheneacetamide; mp. 241 °C.

EXAMPLE XLV A mixture of 4.5 parts of N-(l-cyclopentyl-4-piperidinyl)2-pyrimIdinamine, 3.4 parts of 3-methylbenzeneacetyl chloride, parts of sodium carbonate and 180 parts of dimethylbenzene is stirred and refluxed for 17 hours. Another 9 parts of 3-methylbenzeneacetyl chloride is added dropwise. Upon completion, stirring is continued for 67 hours at reflux temperature. The reaction -5043802 mixture is cooled, water is added and the layers are separated.

The organic phase is extracted with a diluted hydrochloric acid solution. The combined aqueous phases are washed with benzene and alkalized with a diluted 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 off and crystallized twice: first from ethanol and then from methanol, yielding 1 part of N-(l-cyclopentyl-4piperidinyl)-3-methyl-N-(2-pyrimidinyl)benzeneacetamide ethanedioate; mp. 204.1*C.

EXAMPLE XLVI Following the procedure of Example XLV and using equivalent amounts respectively of an appropriate N-aryl-4-piperidinamine and of an appropriate arylacetyl chloride as starting materials, the following compounds are obtained in base form or in the form of an. acid addition salt after treatment with the appropriate acid: Ar L Ar Ar1 base or salt form mp. 0 3-pyridinylC6H5 (E)-2-butenedioate 219.6*0 E> 3-pyridinyl 3-CH3-C6H4 (E)-2-butenedioate 250.3’C 0 2-pyridinyl 3-Cl-C6H4 (cooh)2 205.9°C [> 2-pyridinyl 3-CH3-C6H4 base 107.8’C -51438θ^ L Ar Ar1 base or salt form mp. D- 2-pyridinyl 4-Cl-C6H4 base 119.2°C D- 2-pyridinyl 2-thienyl base 129,4’C D· 2-pyridinylC6H5 base 108.8’C D- 2-pyrimidinylC6H5 (cooh)2 223.5’C (ch3)2-ch- 3-pyridinylC6H5 . base 129.4’C (ch3)2-ch- 3-pyridinyl 6 4 base 117. 7’C (ch3)2-ch- 3-pyridinyl 4-Cl-C6H4 base 146.6’C (ch3)2-ch- 3-pyridinyl 2-thienyl base 126. 7*C (ch3)2-ch- 3-pyridinyl 3-CH3-C6H4 base 100’C (ch3)2-ch- 2-pyridinyl 3-Cl-C6H4 base 102.6’C (ch3)2-ch. 2-pyridinylC6H5 base 72.1’C (ch3)2-ch- 2-pyridinyl 4-Cl-C,H„ 6 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 (cooh)2 196,l’C (ch3)2-ch- 2 -pyr i midinyl 4-Cl-C6H4 (cooh}2 195.7’C EXAMPLE XLVII A mixture oi 5 parts of methyl l-(l-methylethyl)-4(phenylamino)-4-piperidinecarboxylate, 24 parts of 4-chlorobenzeneacetyl chloride, 4 parts of sodium carbonate and 180 -5243802 parts of dimethylbenzene is stirred and refluxed for 32 hours.

The reaction mixture is cooled, washed with a diluted sodium hydroxide solution and extracted with a diluted hydrochloric acid solution: three layers are obtained. The oil and the aqueous phase are combined and alkalized with a diluted 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 off and crystallized from a mixture of 2-propanol and 2,2'-oxybispropane, yielding 5 parts (48 %) of methyl 4-/N(4-chlorophenyl)acetyl-N-phenylaminq7-l-(l-methylethyl)-4piperidinecarboxylate ethanedioate; mp. 154,2 °C, EXAMPLE XLVIII Following the procedure of Example XLVII and using equivalent amounts respectively of an appropriate 4-arylamino-4piperidinecarboxylate and of an appropriate arylacetyl chloride as starting materials, the following compounds are obtained in free base form or in the form of an acid addition salt after treatment with the appropriate acid: L Ar1 R base or salt form mp. (ch3)2-ch- 3-CH3-C6H4C2H5 (COOH)2 198.4"C (CH3)2-CH-C6H5C2H5 (E)-2-butene- dioate 168.5’C -534 3 8θ2’ L Ar1 . R base or salt form mp. (CH3)2-eH- 2-thienylC2H5 (cooh)2 156.8°C (ch3)2-ch- 4-Cl-C6H4C2H5 HC1 191.5°C (ch3)2-ch- 3-CH3-C6H4 ch3 (cooh)2 170eC (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 D- 4-Cl-C6H4C2H5 (E)-2-butenedioate 195.6’CC6H5C2H5 (E)-2-butenedioate 203.3’C D- . 3-C1-C6H4C2H5 (E)-2-butenedioate 207.8’C D· • 3-CH3-C6H4C2H5 (E)-2-butenedioate 188.1’C D-C6H5 ’ ch3 (cooh)2 197.2’C 0 2-thienylCI 3 (cooh)2 166,4’C E> 3-Cl-C6H4 ch3 base 94° C D- 3-CH3-C6H4 ch3 (cooh)2 189.5’C EXAMPLE IL To a stirred mixture of 4.4 parts of l-(l-methylethyl)-Nphenyl-4-piperidinamine, 5.3 parts of sodium carbonate and 180 parts of benzene are added dropwise 5 parts of benzeneacetyl chloride.

Upon completion, stirring is continued overnight at reflux. The reaction mixture is cooled, washed successively with water, a sodium hydrogen carbonate solution and again with water, dried, -5443802 filtered and evaporated. The residue is converted into the hydrochloride salt in-2, 2*-oxybispropane and 2-propanol. The formed salt is filtered off and crystallized from a mixture of 2-propanol and 2, 2'-oxybispropane, yielding 2.5 parts of N-/l-(l-metliylethyl)-4-piperidinyl75 N-phenylbenzeneacetamide hydrochloride; mp, 184,4’C, EXAMPLE L Following the procedure of Example IL and using equivalent amounts respectively of an appropriate N-aryl-4-piperdinamine and of an appropriate arylacetyl chloride as starting materials, the following compounds are obtained in base form or in the form of an acid addition salt after treatment with the appropriate acid: L Ar Ar1 base or salt form mp, (ch3)2-ch-C6H5 3-CH3-c6H4 HC1 173.6 (ch3)2-ch-C6H5 3-Cl-C6H4 HC1 204, 8 (ch3)2-ch-C6H5 2-thienyl (E)-2-butenedioate 168.1 ch3 2,6-(CH3)2-C6H3C6H5 base 95.5’1 ch3 4-Cl-C6H4C6H5 base 115’C C2Hg 4-Cl-C6H4 3-OCHj-C6H4 base 90. 7°' nC3H? 2,6.(CH3^-C6H3 2-thienyl (cooh)2 153’C -5543802 L Ar Ar1 base or salt form mp. nC3H7' 2, 6-(CH3)2-C6H3C6H5 (cooh)2 161’C CH2=CH-CH2 4-Cl-C6H4 2-thienyl . HC1 227.5’C ’ D-C6H5 4-Cl-C6H4 base 125.l’C ?C6H5 3-CH3-c6H4 (E)-2-butenedioate 161.3’C D·C6H5 2-thienyl base 119’C 0C6H5 3-Cl-C6H4 base 121.8’C D-C6H5C6H5 . base 139.8’C 3-pyridinyl 4-Cl-C6H4 base 149.9’C D- 3-pyridinyl 3-Cl-CzH. 6 4 2HCl.l/2H2G 236.6’C D- 3-pyridinyl 2-thienyl base 159.8’C ΦC6H5 4-Cl-C,H. 6 4 HC1 265.8’C ®-C6H5 3-Cl-C6H4 HC1 255.4’C EXAMPLE LI | A suspension of 1,25 parts of sodium amide in 56 parts of ( ) benzene is stirred under nitrogen atmosphere and warmed to a temperature oi 40°C. Then there is added dropwise a solution of 6 parts of N-(4-chlorophenyl)-l-(l-methylethyl)-4-piperidinamine in 56 parts of benzene. Upon completion, the whole is stirred and refluxed for I6h, 45. The mixture is cooled to 25^0 and there is added a mixture of 7.8 parts of 3, 4-dichlorobenzeneacetyl chloride in 88 parts of benzene. After stirring and refluxing for 2 additional hours, the reaction mixture is cooled and 80 parts of water are added. The whole is acidified with a diluted hydrochloric acid solvdon. The -5643802 aqueous acid phase is alkalized 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 1,1'-oxybisethane and 120 parts of hexane. The solution is cooled overnight at -10eC, filtered from some impurities and the filtrate is evaporated again. The residue is dissolved in 120 parts of 1,1'-oxybisethane, treated with activated charcoal, filtered and evaporated. The latter residue is crystallized from hexane at -lO’C, yielding 2.2 parts of 3,4-dichloro-N-(4-chlorophenyl)-N-/r-(lmethylethyl)-4-piperidiny£7benzeneacetamide; mp. 101.7’C.

. EXAMPLE LII Following the procedure of Example LI and using equivalent amounts respectively of an appropriateN-aryl-4-piperidinamine and of an appropriate arylacetyl chloride as starting materials, the following compounds are obtained in base form or in the form of an acid addition salt after treatment with the appropriate acid: 4-bromo-N-(4-chlorophenyl)-N-/l-(l -methylethyl)-4-piperidir.yl7henzeneacetamide; mp. 118.1°C; 4-chloro-N-(2,6-dimethylphenyl)-N-/r-(l-methylethyl)-4-piperidinyf7benzeneacetamide hydrochloride; mp. 268.2*C; and N-(4-chlorophenyl)-4-(l -methylethyl)-N-/l-(l -methylethyl)-4piperidinyljbenzeneacetamide; mp. 104.9°C.

EXAMPLE LIII Parts of 4-chloro-N-(4-chlorophenyl)-N-/l-(1-methyl-, ethyl)-4-piperidinyl7benzeneacetamide are dissolved in a mixture of 60 parts of 1,1’-oxybisethane and 16 parts of 2-propanone. The -5743 8 0 resulting solution is acidified, with an excess of 2-propanol previouslysaturated with gaseous hydrogen chloride. The precipitated salt is filtered off and dried, yielding 7.5 parts of 4-chloro-N-(4-chlor9phenyl)N-/l -(1 -methylethyl)-4-piperidinyl7benzeneacetamide hydrochloride; mp. 266.6°C.

EXAMPLE LIV From 6 parts of N-/T-(l-methylethyl)-4-piperidiny£7-Nphenyl-2-thiopheneacetamide (E)-2-butenedioate, the free base is liberated in the conventional manner with a diluted 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-/T-(l-mdthylethyl)-4-piperidinyl7N-phenyl-2-thiopheneacetamide ethanedioate; mp, 167.4°C.

EXAMPLE LV From an aqueous solution of 2. 8 parts of N-(2, 6-dimethylphenyl)-N-(l-propyl-4-piperidinyl)-2-thiopheneacetamide dihydrochloride, the free base is liberated by alkalization with sodium hydrogen carbonate solution. The free base is extracted with 1,1'-oaybisethane. The extract is dried and evaporated. The oily residue is dissolved in 56 parts of hexane and after cooling to -I0eC, the solid free base is precipitated. It is filtered off and dried, yielding 1,6 parts of N-(2,6-dimethylphenyl)-N-(l -propyl-4-piperidinyl)-2-thiopheneacetamide; mp, 62.5°C. -5843802 EXAMPLE LVI From 3. 9 parts of N-(l-cyclopentyl-4-piperidinyl)-3methyl-N-(3-pyridinyl)benzeneacetamide (E)-2-butenedioate, the free base is liberated in the conventional manner with a diluted sodium hydroxide solution. After extraction with 2, 2'-oxybispropane, the latter is washed with water, dried, filtered and evaporated. The residue is converted into the ethanedioate salt in ethanol. The sait is filtered off and crystallized from a mixture of ethanol and 2,2r-oxybispropane, yielding 3 parts of N-(l-cyclopentyl-4-piperidinyl)-3-methyl-N(3-pyridinyl)benzeneacetamide ethanedioate; mp. 192. 6’C.

EXAMPLE LVII A mixture of 50 parts of 4-(phenylamino)-l-(phenylmethyl)4-piperidinecarboxamide and 600 parts of a concentrated hydrochloric acid solution is refluxed for 16 hours. After cooling the reaction mixture is concentrated under diminished pressure to a volume of 400 parts, whereupon a precipitate is formed. It is filtered off, washed with water and 2-propanone and dried, yielding 43 parts of 4-(phenylamino)«l-(phenylmethyl)-4-piperidinecarboxylic acid dihydrochloride,· mp, 261-263°C (dec.).

A mixture of 19 parts of 4-(phenylamino)-l-(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 residue is dissolved in water. The aqueous -5943803 solution is alkalized with ammonium hydroxide and extracted with a mixture of methylbenzene and 2, 2'-oxybispropane. The combined organic layers are dried over magnesium sulfate, filtered and evaporated. The oily residue is dissolved in 200 parts of 2,2'-oxybispropane and gaseous hydrogen chloride is introduced into the solution. The precipitated hydrochloride is filtered off, washed with 2-propanol, filtered off again and dried, yielding 11.5 parts of ethyl 4-(phenylamino)-l -(phenylmethyl)-4-piperidinecarhoxylate dihydrochloride; mp. 212-214.4eC.

To a stirred and refluxing solution of 101,4 parts of ethyl 4-(phenylamino)-l-(phenylmethyl)-4-piperidinecarhoxylate in 640 parts of dry benzene is added dropwise a solution of 172 parts of a sodium dihydro-bis(2-methoxyethoxy)aluminate 70% in benzene, in 160 parts of dry benzene. Upon completion, stirring is continued for 2h. 30 at 80°C. The reaction mixture is cooled, poured onto ice-water, alkalized 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 off, boiled 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 liberated in the conventional manner. After extraction with 1,1'-oxybisethane, the latter is washed with water, dried and evaporated, yielding 56.6 parts of 4-(phenylamino)-l-(phenylmethyl)-4piperidinemethanol as an oily residue.

To a solution of 32 parts of 4-(phenylamino)-l-(phenylmethyl)4-piperidinemethanol in 90 parts of benzene are added 0,2 parts of Ν, N, N-triethylbenzenemethanaminium chloride and 150 parts of a sodium hydroxide solution 60%. After stirring vigourously, there are 6043802 added dropwise 10. 9 parts of dimethyl sulfate at a temperature below 30’C. Upon completion, stirring is continued at room temperature, first for 2h. 30 and. further, after the addition of a second portion of 2. 6 parts of dimethyl sulfate, for Ih. 30. 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% of methanol, saturated with ammonia, as eluent. The pure fractions are collected and the eluent is evaporated, yielding 24. 8 parts of 4-(methoxymethyl)N-phenyl-l-(phenylmethyl)-4-piperidinamine as a residue.

A mixture of 10 parts of 4-(methoxymethyl)-N-phenyl-l-(phenylmethyl)-4-piperidinamine and 200 parts of acetic acid is hydrogenated at normal pressure and at room temperature with 2 parts of palladiumon-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The oily residue is dissolved in water, cooled and .alkalized with ammonium hydroxide. The product is extracted with trichloromethane. The extract is washed with water, dried, filtered and evaporated. The oily residue is purified hy column-chromatography over silica gel using a mixture of trichloromethaae and methanol (90:10 by volume) saturated with gaseous ammonia, as eluent. The pure fractions are collected and the eluent is evaporated, yielding 4.5 parts of 4-(methoxymethyl)-Nphenyl-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 refluxed for 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 thoroughly with water, dried, filtered and evaporated. The residue . -614 3 8 0 2 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, yielding 5. 7 parts (42. 6%) of 4-(methoxymethyl)-l-(l-methylethyl)-N-phenyl-4-piperidinamine as an oily residue.

To a stirred mixture of 5.5 parts of 4-(methoxymethyl)-l(l-methylethyl)-N-phenyl-4-piperidinamine in 56 parts of benzene is added dropwise a solution of 13.8 parts of benzeneacetyl chloride in 45 parts of benzene at 26-32eC. Upon completion, stirring is continued first for one hour at 26-32°C and further for 3. 60 hours at 3855°C. After cooling, the precipitated product is filtered off and converted into the hydrochloride salt in a mixture of 2-propanol and 2propanone (5:1 by volume). The salt is filtered off 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, yielding 1.05 parts of N-/?-(methoxymethyl)l-(l-methylethyl)-4-piperidinyl7-N-phenylbenzeneacetamide hydrochloride; mp. 249.1°C.

EXAMPLE LVUI By repeating the procedure of steps 1 through 4 of Example LVII and by using an equivalent amount of an appropriate di(lower alkyl) sulfate in step 5 thereof the following intermediates are prepared from the appropriate starting materials: 4-(methoxymethyl)-N-(3-methylphenyl)-l-(phenylmethyl)-4-piperidinamine; 4-(methoxymethyl)-N-(4-methylphenyl)-l-(phenylmethyl)-4-piperidinamine: 4-(methoxymethyl)-N-(2 -methylphenyl)-1 -(phenylmethyl) -4-piperidinamine; -62N-(4-fluorophenyl)-4-(methoxymethyl)-l -(phenylmethyl)-4-piperidin amine; 4-{ethoxymethyl)-N-phenyi-l -(phenylmethyl)-4-piperidinamine; and 4-(ethoxymethyl)-N-(4-fluorophenyl)-l -(phenylmethyl)-4-piperidin5 amine.

EXAMPLE L1X Following the procedure of step 7 of Example LVII and using therein equivalent amounts of respectively an appropriate N-aryl-4(lower alkyloxymethyl)-l-(phenylmethyl)-4-piperidinamine and an appropriate arylacetyl chloride as starting materials the following intermediate products are prepared: N-24-(methoxymethyl)-l -(phenylmethyl)-4-piperidinyl7-N- phenyl benzeneacetamide; N-2£-(methoxymethyl)-l ~(phenylmethyl)-4-piperidinyl7-N-(3-methyl15 phenyljbenzeneacetamide; N-/4-(methoxymethyl)-1 -(phenylmethyl)-4-piperidinyl7 -N-(4-methylphenyl)benzeneacetamide; Ν-/Ϊ-(methoxymethyl)-1 -(phenylmethyl)-4-piperidinyl7-N-(2 -methylphenyl)benzeneacetamide; N-(4-fluorophenyl)-N-^-(methoxymethyl)-l-(phenylmethyl)-4-piperiΝ-/Ϊ- (ethoxymethyl) -1 - (phenylmethyl) -4 - piperidinyl/-N- phenylbenz ene acetamide; -634 3 8 0 2 N-,/i-(0thoxymethyl)-l-(phenylmethyl)-4-piperidinyl7-'N(4-fluorophenyl) benzeneacetamide; N-/4-(methoxymethyl)-l-(phenylmethyl)-4-piperidinyl7-N-phenyl-4methylbenzeneacetamide; N-^-(methoxymethyl)-l-(phenylmethyl)-4-piperidinyl7-N-phenyl-4methoxybenzeneacetamide; and N-/4-(methoxymethyl)-l-(phenylmethyl)-4-piperidinyl7-N-phenyl-2thiopheneacetamide.

EXAMPLE LX Following the procedure of step 5 of Example LVII the following compounds are prepared starting from the appropriate phenylmethyl substituted precursors: N-/5-(methoxymethyl)-4-piperidinyl7-N-phenylbenzeneacetamide; N-^i-(methoxymethyl)-4-piperidinyl7-N-(3-methylphenyl)benzeneacetamide; N - /4-(methoXymethyl) -4-piperidinyl7-N-(4-methylphenyl)benzene acetamide; N-^T-(methoxymethyl)-4-piperidinyl7-N-(2-meth.ylphenyl)benzeneacetamide; N-(4-fluorophenyl) -N - /4-(methoxymethyl) -4-piperidinyl7benzeneacetamide; N-/i-(ethoxymethyl)-4-piperidinyl7-N-phenylbenzeneacetamide; -6443803 N-/i-(ethoxymethyl)-4-piperidinyl/’-N-(4-fluorophenyl)benzeneacetamide; N-/4-(methoxymethyl)-4-piperidinyl7-N-phenyl-4-methylbenzene~ acetamide; N-^-(methoxymethyl)-4-piperidinyl/-N-phenyl-4-methoxybenzeneacetamide; and N-/4-(methoxymethyl)-4-piperidinyl7-N-phenyl-2-thiopheneacetamide.

EXAMPLE LXI To a stirred mixture of 7.5 parts of N-(4-chlorophenyl)l-(l-methylethyl)-4-piperidinamine and 80 parts of 4-methyl-2pentanone are added dropwise 9 parts of ^-(2-chloro-2-oxoethyl)phenyl/ ethyl carbonate. Upon completion, the whole is heated to reflux and stirring is continued for one 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 over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions are collected and the eluent is evaporated, yielding 5.5 parts of ^4-^-^ (4-chlorophenyl)/T-(l-methylethyl)-4-piperidinyl7amino j-2-oxOethyl/phenylJ ethyl carbonate as an oily residue. -65^4 - jz-| (4 - chlor ophenyl) /Γ1 -2-oxo enyl ( ethyl A mixture of 5. 5 parts of |4 (1 -methylethyl)-4-piperidinyl/aminoj - carbonate and 50 parts of a 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 over silica gel using a mixture of trichloromethane and methanol (80:20 by volume) as eluent. The pure fractions are collected and the eluent js evaporated. The oily residue is converted into the hydrochloride salt in 4-methyl-2-pentanone. The salt is filtered off and dried in vacuo for 12 hours at 60°C, yielding 1.9 parts of N-(4-chlorophenyl)~4-hydroxy-N-/T"(l -methylethyl)-4piperidinyl/benzeneacetamide monohydrochloride: mp. 242.9°C.

Claims (4)

1. An N-aryl~N-(4-piperidinyl)arylacetamide having the general formula: X Ar wherein: 5 L is a hydrogen atom, an alkyl group having from 1 to 10 carbon atoms, a cycloalkyl, cycloalkyl-lower alkyl or lower alkenyl group; Ar is a phenyl, mono- or di-substituted phenyl, pyridinyl or 2-pyrimidinyl group, wherein each substituent in the mono- and di-substituted phenyl is independently a halogen atom or a lower alkyl group; Ar' 1 ' is a phenyl, mono- or di-substituted phenyl, or thienyl group, wherein each substituent in the mono- or disubstituted phenyl is independently a halogen atom, a . lower alkyl, hydroxy or lower alkyloxy group; and X is a hydrogen atom, a lower alkyloxycarbonyl or lower alkyloxymethyl group.

2. N-(4-Chlorophenyl)-N-[1-(1-methylethyl)-4piperidinyl] benzeneacetamide. 0

3. N-(4-chlorophenyl)-N-(l-ethyl-4-piperidinyl)benzeneacetamide. 4 3 8 Ο 2 4. 3-Chloro-N-(l-cyclohexyl-4-piperidinyl)-N-phenylbenzeneacetamide. 5. A compound of formula (I) as defined in claim 1 substantially as hereinbefore described with reference to any one of Examples (XVII to XXI, XXIII, XXIV or XXXII to LVII. 6. A pharmaceutically acceptable acid addition salt of a compound as claimed in any one of the preceding claims. 7. A process for preparing an N-aryl-N-(4-piperidinyl)arylacetamide as defined In claim 1, which process comprises (a) eliminating a protecting group P by known methods from a compound of the formula: (IV) in order to prepare a compound of the formula: (I-a) wherein X, Ar and Ar 3 are as defined in claim 1; or b) N-alkylating a compound of formula (I-a) above, by known procedures in order to prepare a compound of the formula: (I-b) 68 ., 3 8 Ο 2 wherein has the definition given for L in claim 1, other than hydrogen, and X, Ar and Ar·*· are as defined in claim 1; or c) preparing a compound of the formula (I-b) wherein the group iA is an alkyl, cycloalkyl or cycloalkyl-lower 5 alkyl group only and the carbon atom attached to the piperidine nitrogen has at least one hydrogen atom thereon, 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 an 10 appropriate catalyst; or d) by reductive elimination of the phenylmethyl group from a compound of the formula: Ar wherein l/ is as defined above, X, Ar and Ar^ are as defined in claim 1, and Y~ is the residue of an acid, using catalytic hydrogenation in order to prepare a compound of the formula (I-b); or e) acylating a compound of the formula; wherein ΐΛ is as defined above and X and Ar are as defined in claim 1, with an appropriate arylacetyl halide of the formula: (Ill) 43 802 halo-C-CH 2 -Ar 1 wherein Ar 1 is as defined in claim 1, in a suitable reactioninert organic solvent, or £) preparing a pharmaceutically acceptable acid addition salt of the product of any one of steps a) to e). 8. A process as claimed in claim 7 wherein in step (e) when Ar 1 in the final compound (I-b) is a mono- or di-hydroxyphenyl group, alone, or together with other substituents, an appropriate protecting group is added to the hydroxy group or hydroxyl groups on the starting compound (III), and the protecting group or groups are removed by alkaline hydrolysis from the final product. 9) A process as claimed in claim 7 wherein in step (b) the N-alkylation is conducted by reacting the compound (I-a) with an appropriate reactive ester of the formula L 1_ Y, wherein Y is an appropriate reactive ester radical. 10. A process as claimed in claim 7 wherein the reaction in step (e) is carried out in the presence of a base. 11. A process as claimed in claim 9 wherein the N-alkylation is carried out in the presence of a base. 12. A process for preparing N-(4-chlorophenyl)-N[l-(l-methylethyl)-4-piperidinyl)benzeneacetamide or a pharmaceutically acceptable acid addition salt thereof, which comprises reacting N-(4-chlorophenyl)-N-(4-piperidinyl) benzeneacetamide with 2-bromopropane, and, if desired, preparing a pharmaceutically acceptable acid addition salt of the product thereof. - 70 S 8 Ο 2 13. A process for preparing N-(4~chlorophenyl)-N(l-ethyl-4-piperidinyl)henzeneacetamide or a pharmaceutically acceptable acid addition salt thereof, which comprises reacting N-(4-chlorophenyl)-N-(4-piperidinyl)henzeneacetamide 5 with iodoethane, and, if desired, preparing a pharmaceutically acceptable acid addition salt of the product thereof. 14. A process for preparing 3-chloro-N-(l-cyclohexyl-4piperidinyl)-N-phenylbenzeneacetamide or a pharmaceutically acceptable acid addition salt thereof, which comprises reacting 10 l-cyolohexyl-N-phenyl-4-piperidineamine with 3-chloro-benzene acetyl chloride, and, if desired, preparing a pharmaceutically acceptable acid addition salt of the product thereof. 15. A process as claimed in claim 7 substantially as hereinbefore described with reference to any one of the 15 Examples XVII to XXI, XXIII, XXIV, or XXXII to LVII. 16. A compound as claimed in claim 1 whenever prepared by a process as claimed in any one of claims 7 to 15. )7. A pharmaceutically acceptable salt as claimed in claim 6 whenever prepared by a process as claimed in any 20 one of claims 7 to 15. 18. A pharmaceutical composition which comprises a compound as claimed in any one of claims 1 to 5, or claim 16, or a pharmaceutically acceptable salt as claimed in claim 6 or claim 17. together with a pharmaceutically acceptable diluent or 25 carrier. 19. An N-aryl-N-(4-piperidinyl)arylacetamide having the general formula: X L- II (I) N-C-CH 2 -Ar' Ar

4. 3 8 0 2 wherein L is an alkyl group having from 1 to 10 carbon atoms, a cycloalkyl, cycloalkyl-lower alkyl or lower alkenyl group; Ar is a phenyl, mono- or di-substituted phenyl, pyridinyl or 2-pyrimidinyl group, wherein each substituent in the mono- and di-substituted phenyl is independently a halogen atom or a lower alkyl group; Ar is a phenyl, mono- or di-substituted phenyl, or thienyl group, wherein each substituent in the monoor di-substituted phenyl is independently a halogen atom, a lower alkyl or lower alkyloxy group; and X is a hydrogen atom or a lower alkyloxycarbonyl group.