CA1068271A - N-aryl-n-(1-l-4-piperidinyl)-arylacetamides - Google Patents

Abstract

NOVEL N-ARYL-N-(1-L-4-PIPERIDINYL)-ARYLACETAMIDES.

ABSTRACT OF THE DISCLOSURE:
Novel N-aryl-N-(1-L-4-piperidinyl)-arylacetamides useful as antiarrhythmic agents and methods of preparing the same.

Description

8ACKC;~ OUND OF THE IN~rENTION:

This i~ ~en~o~ pertaills to .he ield of N-aryl-~-(A-pip~ridinyl)-rylaceta~nide~. In the prior art there may be fot:nd ~ome N-a~yl-~-(4-pipesidi3yl)amide~ ha~nng analgesic activity. A~umbe. of such eompourlds may be found in the following references~

-,, ~;v . . _., I

.
, . . . , ~ ~ , , , , . ~ . ,. .. " ., ~ - . . ~ , , , , ---` 10~;8271 U.S.Pat. No. 3,164,600; and C.A., 77, 34349a (1g72).

Among other points of difference the antiarrhythmic compounds of this invéntion differ from such known compounds by the nature of the aryl-acetamide group attached to the 4-position of the piperidine nucleus.

DESCRIPTION OF THE PREFERRED EMBODIMENTS:

The novel N-aryl-N-(l-L-4-piperidinyl)arylacetamides with which this invention is concerned may structurally be represented by the formula:

L~ -C-CH2_Arl ( ) Ar L`'`

and the pharmaceutically acceptable acid addition 6alts thereof, wherein: ~
.
L i~ a member selected from the group consisting of hydrogen, aLkyl having from 1 to 10 carbon atoms, cycloallcyl, cycloalkyl-lower alkyl and lower alkenyl;

Ar is a member selected from the group con6isting of phenyl, mono-and di-substituted phenyl, pyridinyl and 2-pyrimidinyl, wherein each substituent in said mono- and di-sub6tituted phenyl i~ independently selected from the group consi6ting ~- ~ of halo and lower alkyl;

Arl is a member selected from the group con6isting of phenyl, mono-and di-substituted phenyl, and thienyl, wherein each sub-stituent in ~aid mono- and di-substituted phenyl i6 in-` ~ dependently selected from the group consisting of halo, lower alkyl, hydroxy and lower alkyloxy; and .

.

~ ~68271 X i8 a member selected from the group consisting of hydrogen, lower alkyloxycarbonyl and lower alkyloxymethyl.

More particularly,the term "alkyl" as used in the definition of L is meant to include straight and branch chained saturated hydrocarbon radicals having therein from 1 to 10 carbon atoms, such as, for example, methyl, ethyl, l-methylethyl, propyl, l-methylpropyl, butyl, 2-methylbutyl, 1,1-dimethylethyl, pentyl, hexyl, heptyl, decyl and the like alXyls; "lower alkyl" as used in the foregoing and in sub-sequent definitions refers to straight and branch chained a~kyl radicals having from 1 to about 6 carbon atoms, such as, for example, methyl, ethyl, 2-methylethyl, propyl, butyl, pentyl, hexyl and the like; "lower allcenyl" refers to a~kenyl radicals having from 3 to about 6 carbon atoms, such as, for example, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl and the like; the term "cycloalkyl" refers to cyclic hydro-car~an radicals having from 3 to 6 carbon atoms, such as, cyclo-propyl, cyclobutyl, cyclopentyl and cyclohexyl; and the term "halo"
is generic to halogens of atomic weight less than 127, i. e. fluoro, chloro, bromo and iodo. ~ .

The subject compounds of formula ( I ) wherein Ar, Arl and X are as previously defined and L is hydrogen, ( I-a ), may generally be prepared starting from a piperidine derivative of formula ( II ), wherein Ar and X are as previously defined and P is an appropriate protecting group such as, for example, phenylmethyl, lower alkyl-oxycarbonyl or phenylmethoxycarbonyl, by first acylating ( II ) with an appropriate aryla¢etyl halide of formula ( III ), preferably the chloride, .
~: and thereafter eliminating the protecting group P of the thus obtained f IV ) following rt-kno_ procedures.

:

` 1068271 P-N~ I H ~ halo-C-CH2-Arl acylation Ar (II) (III) `

X '.
P-N~N- C - CH -Ar elimination of

2 protecting group Ar ( IV ) HN5(1-C-CH2-Ar r ~.

tI_a) The acylation of ( II ) with ( III ) may be carried out following art-known N-acylating procedures, 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 such a~, for example, benzene, methylbenzene and dimethylbenzene, ; and halogenated hydrocarbons such as trichloromethane. Appropriate base~ include, for example, al~cali metal carbonates and hydrogen carbonates, aL~cali metal amide~ such as sodium amide, and organic 19 base6 such as, for example, pyridine and N,N-diethylethanamine.
The elimination of the protecting group P may be per-fo~med according to generally known methQdologies. When the pro-tecting group is phenylmethyl or phenylmethoxycarbonyl it is easily remoYed 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 :

`

106827:1 trong mineral acid, e. g., hydrochloric, hydrobromic or sulfuric acid and alkaline hydrolysis is conveniently carried out using alcoholic alkali, e . g . potas sium hydroxide in 2 -propanol.
'.

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

Conveniently said N-alkylation- may be achieved by reacting ( I-a ) with an appropriate reactive ester of the formula L -Y, ( V ), wherein Ll is as defined hereinabove and Y i8 an appropriate reactivs ester radical such as, for example, halo, or a sulfonyl radical æuch a~ methanesulfonyl or 4_methylbenzenesulfonyl. The foregoing reaction may be carried out in the usual manner, or example, by stirring and reflwcing the reactants together in an appropriate reaction-inert organic solv0nt such as, for example, a lower alkanol, e. g., methanol, ethanol, propanol, butanol and the like alcohols; an aromatic hydro- `~
carbon, e. g. benzene, methylbenzene, dimethylbenzene, and the like;
a ketone, e. g., 4-methyl-2-pentanone; an ether, e.g., 1,4-dioxane, 1, 1 ' -oxybisethane and the like; N, N-dimethylormamide; nitrobenzene;
and the like. In order to bind the acid which i8 liberated durir~g the - course of the reaction there may be added an appropriate base 8uch as, for example, sodium or potassium carbonate or hydrogen carbonate or an organic base such as, or example, N,N-diethylethanamine. 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.

~ ' _5_ ., , ~ .

-10682'71 . ` . ` i .
When L in the compounds ( I-b ) has the meaning of alkyl, cycloalkyl or cycloaL~cyl-lower alkyl and when the carbon atom attached to the piperidine nitrogen has thereon at least one hydrogen atom, the introduction of said L may equally well be performed by catalytic hydrogenation of a mixture of an appropriate aldehyde or ketone corres-ponding to the alcohol Ll -OH, and a compound of formula ( I-a ) in the presence of an appsopriate catalyst such as, for example, palladium-on-charcoal. In order to improve the 6electivity of the hydrogenation reaction there may be added to the mixture a small amount of an appro-priate catalyst poison such as, for example, thiophene.

Alternatively the compounds ( I-b ) may be obtained by the reaction of L Y with a phenylmethyl-substituted compound of formula ( II-l ) to form a quaternary piperidinium salt of formula (VI ), and subsequent reductive elimination of the phenylmethyl group. The quater- 1 -nization reaction may be carried out, for example, by heating the ' reactants together in an appropriate ~olvent, such as acetonitrile, and elimination of the phenylmethyl group may be performed by catalytic s hydrogenation using palladium-on-charcoal catalyst. The foregoing reaction~ are illustrated in the following ~chematic representation.

L -Y ~ k~CH -N/~ R
\=J 2 ~ -C-CH2-Arl acetonitrile (V) Ar (II-I ) : . ` .

~3CH/~-C-cH2-Arl~ y~ ~ ~ C ~ (I-b) ( VI ) - . :

106827~

Still another method of preparing the compounds of formula ( I-b ) consists in acylating an appropriate N-aryl~ Ll -4-piperidin-amine of formula ( VII ) with an appropriate arylacetyl halide of formula ( III ) according to well-known N-acylating procedures as described hereinabove for the preparation of ( IV ) starting from ( II ) and ( III ).

Ll N~( I H (III ) > (I-b ) Ar ( VII ) When Arl in the compounds (I-b ) has the meaning of a sub-stituted phenyl group having as substituents one or two hydroxylgroups, alone or together with other substituents, it is appropriate to protect said hydroxylgroups in the corresponding starting materials (III ) with an appropriate protecting group such as lower alkyloxycarbonyl, where-upon a corresponding derivative of (I-b) is obtained, the protecting group of which i~ easily removed by alkaline hydrolysis using for ex- !
ample diluted aqueous alkali.

The subject compound may be converted to the pharma-ceutically acceptable acid addition salt form by treatment with an appropriate acid, such as, for example, an inorganic acid, such as `~
hydrohal~cacid, e. g., hydrochloric, hydrobromic, and the like, and ; ~ sulfuric acid, nitric acid, phosphoric acid and the like; or an organic acidj such as, for example, acetic, propanoic, 2-hydroxyacotic, 2-hydroxypropanoic, 2-oxopropanoic, propanedioic, butanedioic, (Z)-2-butenedioic, (E)-2-butenedioic, 2-hydroxybut~nedioic, 2, 3-dihydroxy-butanedioic, 2-hydroxy-1, 2, 3-propanetricarboxylic, benzoic, 3-phenyl-2-propenoic, x-hydroxybenzeneacetic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfamic, 2-hydroxybenzoicj 4-amino-2-hydroxybenzoic and the like acids. Con-versely, ~he salt form can be converted by treatment with alkali into the free base form.
.

_ 7 _ - .
:~

: , . . : , . ,. , . - . .
, . . , . . ~ ..... .
.. . . . .

The intermediates used a6 starting materials in the foregoing preparations, a number of which are known compounds, may be pre-pared as follow~.

The intermediate6 of formula (II ) wherein X ~tands for hydrogen, (II-a), are conveniently obtained a6 follows. A 4-piperidin-one of formula (VIII ), having in the 1 -position an appropriate protecting group P, i8 subjected to a condensation reaction with an appropriate '~
arylamine ( IX ), e, g. by 6tirring and refluxing the reactants under ,~
azeotropic water removal in an appropriate organic solvent, preferably an aromatic hydrocarbon such as benzene, methylbenzene or dimethyl-benzene in the presence of an appropriate acid such as, or example, 4-methylbenzene~ulfonic acid, acetic acid, hydrochloric acid and the like. The resulting Schiff base (X) is then reduced with an appropriate reducing agent such a~, for example, sodium borohydride, or by catalytic hydrogenation using, for example, platinum oxide catalyst, to obtain the corresponding N-aryl-4-piperidinamine (II-a).

The foregoing reactions are more clearly illustrated in the following schematic representation:

3=0 + H2N-Ar > P_N3N-Ar (VIII ) (IX ) (X ) :
NaBH4 > ( II-a ) Intermediates of formula ( VII ) wherein X is hydrogen, ( VII-a), ZO are conveniently prepared starting from ( II-a ~ by first eliminating theprotecting group P in the usual manner to obtain a N-aryl-4-piperidin-amine of formula ( XI ) and thereafter introducing the Ll -substituent as described hereinbefore for the preparation of(I-b) starting from(I-a).

_ .......... . . . , .. . ~

When Ll in the intermediates (VII-a ) has the meaning of a methyl group, (VII-a-l )j they may directly be obtained by the reduction of an intermediate ( II-a ) wherein P is a lower alkyloxycarbonyl group, (II-a-2 ), with an appropriate reducing agent such as, for example lithium aluminium hydride. The foregoing reactions are illustrated in the following schematic repre~entation:

~ .
( II-b ) elimination ~ HN~( ~ introductio~ L -N~(H 5 of p ~H of L ~H
Ar Ar ~`
( XI ) - ( VII-a ) ? .
'~ ~

(lower alkyl)-O-e~-N~( 4 ~ CH3-N~( '`

A:r Ar .. ..
( II-a -2 ) ( VII -a -1 ) , Intermediates of formul ( II ) wherein X ~tands for lower alkyloxycarbonyl, (II-b), masr be prepared as followo. ~, l -Phenylmethyl-4_piperidinone ( XII ) is reacted with an ~; 10 ~ appropriate arylamine ( IX ) and an alkali metal cyanide, for example `
potas~ium 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, such as hydrochloric acid, whereby troduction of the nitrile function and of the amine function is effected 15 ~ in the 4-position of the piperidine nucleus, yielding an intermediate of formula ( XIII ).

-9 - . . .

- ~

1(~68Z71 The nitrile (XIII ) is then converted into the amide (XIV ) by acid hydrolysis. Advantageously one may use a concentrated strong, aqueous, inorganic acid for this ~urpose, such as hydrochloric acid, phosphoric acid and, preferably, sul~uric acid. The amide ( XIV ) is then further hydrolyzed to obtain 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., hydro- -chloric or sulfuric acid, or by allcaline hydrolysis using an appropriate base, e. g. sodium or potassium hydroxide. The thus obtained carboxylic acid (XV ) is in turn converted into a metal salt thereof, preferably the sodium salt ( XVI ), by the reaction with alkali, e. g., with 60dium hydro-xide. 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 aL~caline hydrolysis is carried out.
The salt ( XVI ) is then converted into the desired ester ( II-b ) wherein P stands for phenylmethyl ( II-b-l ) by the reaction with an appropriate halo-lower alkane ( XVII ) in an appropriate ~olvent ~uch a~, for example, hexamethylphosphoric triamide.

Alternatively the e6ters ( II-b-~l ) may be prepared by conver-tirlg the acid ( XV ) into an acyl halide ( XVIII ) i~ the usual manner, by the treatment with an appropriate halogenating agent, e. g. with æulfinyl chloride, and reacting 6aid acyl halide with an appropriate lower aL~anol or ~imply by reacting the acid with an appropriate alcohol in the presence of an acid.

The foregoing reaction~ are moro clearly illustrated in the following schematic representation:
- , ~3CH2-N~}o + ( IX ) ~ KCN CH3COOH
water ~; ~ (XII) :
' -(~ CH2-~(NN nitrile-to-amide hydrolysis lr ( XIII ) ~CH -N/--X -NH2 amide-to_acid hydrolysis \~J \_J ~H ~ >
Ar (XIV) ~3CH2-N~( NaOH / lr \ SOC12 (XV) \~

~3CHz-N~ ¦ lowor ~CH2 N~( C-CI
H alkanol IH
lr H+ r ( XVI ) \ / ( XVIII ) halo-lower alkane \ /lower alkanol ( XVII) ~ /
: ~ ~3CH2-~C-O-(lowor alkyl) Ar b-1 3 : ~:

:
:

~ .

The intermediates of formula (II-b ) wherein P stands for lower alkyloxycarbonyl or phenylmethoxycarbonyl (II-b-2 ) are easily derived from ( II-b-l ) by eliminating the protecting phenylmethyl grjoup and thereafter introducing into the thus obtained ( XIX ) the lower al~yloxycarbonyl or phenylmethoxycarbonyl group according to art-known procedures, e. g., by the reaction of (XIX ) with an appropriate lower alkyl or phenylmethyl carbonohalidate, os directly by the reaction of ( II-b-l ) with a lower alkyl or ph~nylmethyl car-bonohalidate whereupon the phenylmethyl group of ( II-b-l ) is re-placed by the desired lower alkyloxycarbonyl or phenylmethoxy-carbonyl group. ~
O , ~.
H ~ J~-0-(lower al~yl) Pd-on-C \~l~H
Ar carbonoha~ ( XIX ) . -lidate \
carbonoha- g-~
lidate ~ ~ / ' ~:, ( II-b-2 ) Intermediates of formula ( VII ) wherein X stands ~r lower alkyloxycarbonyl ( VII-b ) are conveniently prepared by introducing the L -group into an intermediate (XI~ according to the procedures described hereinbefore .
, The intermediates of formulas ( II ) and ( VII ) whorein X
stands for lower alkyloxymethyl, ( II-c ) and (VII-`c ) respectively, '~
may be prepared a3 follows . ,-An appropriate lower a~kyl ester of formula ( II-b ) is re-duced with an appropriate reducing agent such a~, for example, sodium `~
dihydro-bis(2-methoxyethoxy)alumi~ate (Red-Al) in an appropriate organic solvent such as, for example, benzene, or with li~ium boro-hydride to obtain -a 4-piperidinemethanol of formula ( XX ).
- :
:

10ti8271 .` ' Said ( XX 1 is then subjected to an O-alkylation reaction with an appro-priate a~lkylating agent. The O-alkylation step may be carried out by the reaction of (XX ) with an appropriate halo-lower alkane or di-(lower alkyl) 6ulate in an appropriate organic ~olvent such as, for example, benzene, methylbenzene, dimethylbenzene, tetrahydrofuran and the like, in the presence of an appropriate quaternary ammonium salt such as N, N, N-triethylbenzenemethanaminium chloride, yielding the desired intermediate ( II-c ). The intermediate6 (VII-c ) can be prepared by first eliminating the protecting group of t II-c ) and there- t~
after introducing the Ll-substituent into the th~s obtained inter~
mediate (XXI ) according to the procedures described hereinbefore.

Otherwise the intermediates ( VII-c ) may still be prepared by reducing an appropriate alkyl ester of formula (VII-b ) to the cor-responding 4-piperidinemethano-l ( XXII ) in a similar manner a~ de6-cribed hereinabove for the preparation of ( XX ) starting from ( II-b ), and thereafter subjecting ( XXII ) to an O-alkylation reaction with an appropriate lower alkyl alkylating agent according to the procedure6 indicated for the preparation of ( II-c ) starting from ( XX ). f ;
. .
The ~oregoing procedure6 are illustrated heseafter.
O

P-N~A-O-(lower a~kyl) Red_AI P N~CH20H

r Ar b) (XX ) O-aIkylation~CH2-O-(lower alkyl) ~
NH ` -r ; ( II-c) . .

(II_c ) elimination HN~cH2o(low~:r alkyl) introduction of ~H L
Ar ( XXI ) ~ .

Ll N~(CH20(10wer a~kyl) ~H .:
Ar ( VII-c ) ~~

,~:

- LI-N~X (low~ aLICyl) ~ e -Al L1_~3~20}1 Ar Ar ( VII-b ) ( XXII ) O-alkylation (VII

;- ~ ~ . I';`
:. l :

' , .
. : . . . . . . :

.

The compounds of formula (I) and their pharn aceutically acceptable acid addition salts show excellent antiarrhyth~ic properties and as such they are useful in the normalization of irregular cardial rhythms.
The antiarrhythmic effect of the compounds of this in~rention is clearly illustrated in the following experiment in dogs.
The te6t is carried out under neuroleptanalgesia (1 ml per 10 kg bodyweight of entanyl (0. 4 mg/ml) and droperidol (20 mg/ml) ).
About 16 hours after the ligation of the anterior descendent branch of the let coronary artery, dogs oxhibit a muItifocal ~rentricular arrhythmia.
The test compounds were given intraveneously after a control period of 30 minutes, and the following criteria were adopted:

0 : no efect.
.

~ : 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 oi the number of premature beats and increase of the number of normal beats by at least 50% as compared to the control value.
, .
t~ : normalisation of cardial rhythm or decrease of tho num~er of premature beats and increase of the number of normal boats by at lea~t 75% as compared to the control value.

The results obtained in this experiment are given in the fol-lowing tables. The compounds listed therein are not given for the purpose of limiting the invention thereto but only to exemplify the `~
useful antiarrhythmic properties o all the compounds within the scope of formula (I~.
-. .
~ . - , ;
. ~
' -1 5-' ., . ;
~, ' ' ' ' ' ' ' ' ~ . ' .
_~, .. . . . . .

! ~ + + + + ~ ~ , 1 ~ ~ .+ + ~ o + + I + + li .' ¢ n, h ~0 . . ' ~ .
-d ' _I h It VV V V V V V ~ V ~ ~ , ¢ ~ ~

V . _ _ I

~--¢ . ' ' ~ ' I`` .
h ~ t~
~2;J , ¢ V V V V V V V V V V V V , `

~ b V V V V ~-) V V t~ V V ~ ~ ~
V V t.) O V V V V V ~ V t~
, ~

I 1~ p.,~
; ` '` ` '` '~
;~
E~

':

.

` . ` .

- ` 106827`~
.
_ ~ ~ `
.~ ~ + $ + + + + $ `+ $ .~ $ $ $ $ ~ + $
U~ `, '' . ' ``.
b ~ 04 n~, ~ + + + + ` + + + ~ + + + + + + + + + +
$~ U) I + + + + `+ , + + + + + ,~
_ ' . ' ,. ~ ~
b h ~
~ V m ~ V V ~ ~ O V ~ V t.) ~ , ~ ..
` `
~ .
~, fV
~ `D V,~ f,~
_ V V V V V V ~ - ` V, V f`
¢ ~ b .~LI V O V ~ ~ ~ V V O O ~ ' V ~ 1~ ~ V ~ I
.' ~ ~, ~ V ~ V V V
.
.; ' . ,~ v`D V`
p fV. V, V, ~
$ ~ V
b ~
¢` V V V V V O V~ ~ V V V O V~ o ~o V V
' . V ~ V V V O V V V ~ ~ ~ ~ ~ O V
, . ; ,.' . , ~ '.
.

V ~ ~ V V- ~ ) `V V V V O V V V l J, ~: ~ . - .

::: : -' ~
,.

10~8271 ` - ~ -_ . ` .
. ~. ~ ' ' `' ' . . '.
~Ut~o ~ ++ ++ ++ ~ ++ ++ + ~+ + +"I'++ ~ + + ~ j~
~ ~ ~ I ' .

h ~ . I
~lJ ~3 + + + + ~ + + + +
~ ~ + + +~ +'+ + +'+ + + + +, +'+ + I .~, .~ _ I ~ ' h h 0 0 0 0 0 0 0 0 0 0 ` O
O O ~
3 ~ ~ ~ ~ ~ m ~ ~n _ ' .
, ~ m~ m~
~ ~0 ~ 0 ~ o ~D O O i i;-¢ . ~ ~ ~ v ~ ~ m ~ , L
, ~ ' ~ ~ ~ V
, ~ ~ ~ ~ v t~ ~ v ~ . ~ ~
.. . . .. .. .. ...
, ~x~O "
m ~ m ^~
. ~O ~ ~ D ~ ~ ~ C P ~ !h V V ~ V V V V V V
. O V V V V V V V ~ ~,v~ V~D V~ V~
:~ : - - - - `-!
. . ` -, `, : ~p~ XXXXX X,.,X, ~ ~

~ :

``

.

` . .` 1068271 _ ~ ~ . + , ' , . .
C tn + + + + + I + ++ + - ~ + + + $
h ~ - - ~ .
.~ o + o ,+ ~ + + + + + + + +
¢ ~ . ` . ~
_ . , '.

~ _ ~ 0 0 ~ 0 ~ ' `-b h V ~t V ~a ~a t o t t a . . ~ , .

h ~ V ~ V

1~ I ~40v~ o~
- I , `.
.
V`D . V~
b p~
5 v v v ~n ~ v~ vl ~9~3~ j V - ~ V ~ V
~: . ~ .)V ~
, ~ . , . . .
. .

:~: ~ v~ ~V~ v~ n ', V ~ U ~ .~ y ., ., ., ., ., ., y~
1-.... ~.

- - - . , ....

'' ' . ` : ' . . .

iO68Z7i .
,, ~ . . .
~, . ++
n + ~ ~ + +$ + + + _ _ ~ ~ _ h ~I;i ~
Z ~ + $ + ~ $-~ $ ,,+,1 g _ ... o _ ~, ~ g .
h . ~
.
V ~ , iV
~1 ~ ' U~
V ",., i~
d h ,D ~ ,Q .~ ~
. :`
O ~ ~ V~
,....... - ,Q . ~ ..
_ ~ :.
~o ~o ~ D

¢ ~o ~V O ~
,~ , . t~ v ~ , . .
~, . ................................. . ,, . . .
~,, . .
. ' '.

I¢ ~
: ' . ~ ' ' .
l v O ~ y ,$r C ~ C

, - . . , ;
,~- , . : :

'' :~` ' ', ' . ~.. . ... . . . . . . ..
.; ~ : .. .. .

a 1S 1~1 + + + + +

~]
.'' . ~ ~0~ ~ . ~
b O O O

h ua ,a ~
~rl O O O

l5.;~ 5~

~ .
. ~ V ~ o X o o o.~, " ; ~ ~ ~ ¢ ~

1 ~ ' ~ '' ..1"

:':: ' : , ` 10~;8Z71 .`. ' ' ;
. ', ` ~

The following examples are given to illustrate but not to limit the invention thereto. Unless otherwise stated all part~ therein are by wèight.

' ' ;

. . ..
. .

.

EXAMPLE I

A mixture of 19 parts o~ 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. (The reaction vessel i8 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, 21-oxybispropane and evaporated again, yielding 27 parts of N-~-(phenylmethyl)-4-piperidinylidene7-3-pyridinamine a6 a yellow-brown oil.

To a stirred solution of 27 parts of I~-~-(phenylmethyl)-4-piperidinylidene;7-3-pyridinamine in 40 parts of ethanol are added portionwise 3. 8 partQ of 60dium borohydride. Ater the addition i8 complete, the whole is heated to 50C, The solvent i~ evaporated.
The oily residue i~ dissolved in 150 parts of hydrochloric acid lN
and filtered. The filtrate i~ rendered alkaline with ammonium ~-hydroxide and extracted with methylbenzene. The organic layer 18 dried over magnesium sulfate, filtered and evaporated. The solid residue is washed with 2, 2'-oxybispropane and dried, yielding 14 parts o N-~-(phenylmethyl)-4-piperidiny~7-3-pyridinamine;
mp. 131-133C; beige, amorphous powder.

3 ~ :
A mixture of 20 parts o N-~-(phonylmethyl)-4-piporidinyy-3-pyridinamine, 160 partQ of methanol, 30 parts of water. and 12 parts of a concentrated hydrochloric acid solution i8 hydrogenated at 25~ ~ normal pressure and at a temperature between 22-39C, in the pre6ence of 7`parts of palladium-on-charcoal catalyst lO%. After the calculated amount of hydrogen i8 taken up, hydrogenation is stopped.
The catalyst i6 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 :
, ~ . .
" ~ . .

;: :
.~ . - ... , . . .. ~ .. .

106~271 carbonate and evaporated. The æolid residue is recrystallized ~rom a mixture of 40 parts of benzene and 32 parts of 1, 1 '-oxybisethane, yielding 3 parts of N-(4-piperidinyl)-3-pyridinamine; mp. 127-12~C.

EXAMPLE II

. .
A mixture of 171.2 parts of ethyl 4-oxo-1-piperidinecarboxy-late, 159,5 part~ of 4-chlorobenzenamine, 1520 parts of anhydrous methylbenzene and a few cry6tals of 4-methylbenzenesulfonic acid i6 6tirred and refluxed for 7 hours. '(The reaction vessel is provided 'with a renux-condensor and water-6eparator). The methylbenzene 0 i8 evaporated and the oily residue is distilled in vacuo, yielding 192 parts of oily ethyl 4-a4-chlorophenyl)im~no~-1-piperidine-carboxylate; bp. 171-176C at 0.4 mm. pressure.

.
~. . , . i , . , i ' 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 there~n, the following compounds are ... . .
~ ~ obtained: ~

. .
~, ~

~ ~ , CH3-CH2-- 1 -N5=N-Ar ,d . : . .
~ Ar bp. at indicated pressure ~ ..... : __ _ ~ ~ ~,-Cl-C6H4 160-165 C / 0. 5-0. 6 mm.
J ~ ~ ~ 2,6-(CH3)2-C6H3 142-145C / 0.01 mm.
2 -Cl, 6-CH3-C6H3 195 -200 C / 0. 2 mm.

,. . ___~___~_______________ _____________ _____________ ., . ;
;' , ' ' .................... . . .

;~ . .

~068271 `' ' ~ . . . i~
Ar bp. at indicated pres sure . .... ~ .
- 4-F-C6H4 145-147 C / 0. 01 mm.
3, 4~(Cl)2-c6H3 190-200C / 0. 02-0. 03 mm.
3-Cl-C6~4 165-170C /~.01-0.02 mm.
4-Br-C6H4 180-183C /0.1 mm.
2~ 5-(Cl)2-C6H3 _ 2-pyridinyl _ .

EXAMPLE IV
.
A mixture of 171 parts of ethyl 4-oxo-1-piperidine- ,~
carboxylate, 162 part~ of 2,6-dichlorobenzenamine, 800 parts of dimethylbenzene and 1 part of 4-methylbenzenesulfonic acid ~8 ~tirred and sefluxed with water-separator. The reaction mixture iB evaporated, yielding 250 parts of ethyl 4_~2, 6-di-, chlorophenyl)imin~ piperidinecarboxylate as a residue. 1-,'~,''' `', ' ` '' '-- ' , ' ~
. l EXAMPLE V

A mixture of 34 parts of ethyl 4-oxo-1-pipo~idinocarboxyiate, 20 parts of 2-pyrimidinamine, 8 drops of acetic acid and 90 parts of methylbenzene is stirred and re~luxed for 28 hours with water-separator. The reaction mixture is evaporated, yielding 50 parts 20~ of ethyl 4-(2-pyrimidinylimino)-1-piperidinecarboxylate as a ,`
reaidue.

t~

25~

.

t ~;,: , : , . -11~68271 EXAMPLE VI

To a warm solution of 192 parts of ethyl 4-a4-chlorophenyl)-imino7-1-piperidinecarboxylat~in 560 parts of methanol is added portionwise Z3, 5 parts of sodium borohydride at 50C and over a period of one hour. AIter the addition is complete, the mixture îs ~tirred 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-a4-chlorophenyl)amino7-1-piperidinecar-boxylate; mp. 1 15 -1 1 8 C .

" .
, ' . . , '.
.,~ `
EXAMPLE VII
.
Following the procedure of Example VI and u8ing an equivalent amount of an appropriate ethyl 4-arylimino-1-piperidinecarboxylate, the following compounds are prepared:
: . .

CH3-cH2-o-y~-No(NH
I
Ar Ar mp. / bp.
., . ., 2-C1-C6H4 mp. 89-93 C
2-C1; 6-CH3-C6H3 mp. 99. 5C
! ~ 4-F-C6H4 bp. 140-142C /0.01 mm.
.~ 3, 4_tC1)2_C6H3 mp. 113. ~C
;t~ ~ 3-Cl-C6H4 mp. 72 C
4-Br-C6H4 mp. 116. 5C
2~5 (Cl)2-c6H3 mp. 107.2-110.3C
' . 2-pyrimidinyl t ', ' . ' ' ' ' ' ' .
. .
.
.. . .
.'" .

~ , . . ... .: ., ` 1068271 . . .
EXAMPLE VIII

.
To a stirred and refluxing mixture of 250 parts of ethyl 4-a~, 6-dichlorophenyl)imin~7-1 -piperidinecarboxylate in 160 parts of methanol and 160 parts of 2-propanol areadded portionwise 30 parts of sodium borohydride. Upon completion, stirring at reflux temperature is continued for one hour. The warm reaction mixture i8 poured onto water and the product is extracted with methylbenzene.
The extract is dried and evaporated. The residue i8 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~-amino~-l-piperidinecarboxylate; mp. 107.2-il6.6C.

.

EXAMPLE IX
` ` ' A mixture of 45 parts of ethyl 4-a--2, 6-dimethylphenyl)- ~r imlno~-l-piperidinecarboxylate, 0. 3 parts of platinum dioxide in 160 parts of methanol i9 hydrogenated at normal pressure and at a temperature between 24 and 35C. After the calculated amount - of hydrogen i6 taken up, hydrogenation is stopped. The catalyst isiltered off and the filtrate is evaporated. The oily residue is distilled, to yield 30 parts of the oily free base of ethyl 4-~2, 6-dimethylphenyl)amino~ piperidinecarboxylate; bp. 148-153C 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 i8 filtered off and dried, yielding 28. 5 parts of ethyl 4-B2,6-dimethylphenyl)amino~7-1-piperidinecarboxylate hydrochloride;
~; ~ 25 mp. 195.5C.
~ ~ , :
;
s~
'6 ~ ~ _27--.~: , .

l : ' ' . :

1 : .

,:

A mixture of 10 parts of ethyl 4-/~2, 6-dimethylphenyl)amino7-l-piperidinecarboxylate and 135 part~ of hydrobromic acid solution 48%
i~ 6tirred at a temperature between 80 and llOC until the evolution of gaseous carbon dioxide is ceased (about one hour). The red-coloured reaction mixture is evaporated in vacuo. The reæidue is talcen 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 re6ulting semi-~olid residue is '1 triturated in 80 parts of hot 2-propanone and on cooling, the solid product is precipitated, It iæ filtered off, washed ~uccessively with small amounts of absolute ethanol and 2-~ropanone and dried, yielding 13 parts of N-(2,6-dimethylphenyl)-4-piperidinamine dihydrobromide mp. ~ 300 C. `

EXAMPLE X

j To a stirred and cooled (ice-bath) mixture of 165 parts of ethyl 4-(2-pyridinylimino)-1-piperidinecarboxylate and 736 parts of methanol are added portionwise 29. 5 parts of ~odium borohydride (exothermic reaction). Upon completion, 6tirsing is continued for lh, 30 at room temperature. The reaction mixture i8 evaporated.
The residue is suspended in 460 parts of water and the suspension i8 acidified with a concentrated hydrochloric acid solution. The whole i6 alkalized with ammonium hydroxide and the product i8 extracted with methylbenzene. The extract is dried, filtered and ,~ evaporated. The residue is converted into the ethanedioate salt ` 25 in 2-propanol and 2, 2'-oxybispropane. The salt is filtered off, ; washed with 2, 2'-oxybi6propane and dried in vacuo, yieldislg 38 past6 of ethyl 4-(2-pyridinylamino)-1-piperidinecarboxylate éthanedioate .

.
. ' . . .
- -28_ .

, .

A mixture of 90 parts of ethyl 4-(2-pyridinylamino)-1-piperidinecarboxylate, 90 parts of potassium hydroxide and 720 - part~ of 2-propanol is stirred and re1uxed for 2 days. The reaction mixture is evaporated. 1000 Parts o 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 o N-(4-piperidinyl)-2-pyridinamine.

.
.

EXAMPLE XI
.
A mixture of 7 parts of ethyl 4-(2-pyrimidinylamino)-l-piperidinecarboxylate and 120 parts of hydrobromic acid solution 48% i8 stirred and refluxed for 2 hours. The reaction mixture i~
evaporated and the residue is taken up in water. The whole is aLkalizcd with a diluted 60dium hydroxide solution while cooling in an ice-bath, The product is extracted with dichloromethane.
The extract is dried, $1tered and evaporated. The solid residue iæ stirred in 2,2'-oxybispropane, The product i8 filtered off and converted into the hydrochloride salt in 2-propanol. The salt i~ filtered off and cryRtallized fro~ ethanol, yielding 2 parts of N-(4-piperidinyl)-2-pyrimidinamine dihydrochloride hemihydrate;
mp. 268. 5C.
, .
... . . .
EXAMPLE XII
,.', ~:, il ~ .A mixture of 32. 5 parts of methyl 4-(phenylamino)-1-(phenylmethyl)-4-piperidinecarboxylate and 200 part~ of methanol i8 hydrogenated at normal pressure and at room temperature with

5 par$s of palladium-on-charcoal catalyst 10%. A~ter the calculated amount of hydrogen is taken up, the catalyst is filtered off and the '~ iltrate iæ evaporated. The oily residue ~olidifies on scratching in 2, 2'-oxybispropane. The product is $1tered off and dried in ~- 30 vacuo, yielding 20 parts (85%) of methyl 4-(phenylamino)-4-' piperidinecarboxylate; mp. 139.1C.

-29~

106827~ ~
EXAMPLE XIII
..
To a stirred solution of 58 parts of ethyl 4-~4-chloro-phenyl)arnin~-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 40-70C.
Upon completion, the whole is stirred and refluxed for 6h. 15.
The reaction mixture is cooled and filtered. The filtrate is washed succes sively with water, sodium hydrogen carbonate solution and water, then dried and evaporated in vacuo. The residue is crystallized from 1, l'-oxybisethane, yielding 47 parts of ethyl 4-~N-t4-chlorophenyl)-N-(phenylacetyl)amino~_ l-piperidinecarboxylate; mp. 108C.

. .
EXAMPLE XIV
. .. .. .. . . ..
.
- Following the procedure of Example XIII and using equivalent amounts respectively of an appropriate ethyl 4-aryl-amino-l-piperidinecarboxylate and of an appropriate arylacetyl chloride in place of the ethyl 4-a--4-chlorophenyl)amino7-1-pipcridine-carboxylate and benzeneacetyl chloride used therein, the following compounds are prepared:
, ' ' ' `, ¦ ~ ~ CH3-CH2-O C l~)(N-I l-CH2-Ar : :.
, ~

~;: - ' - ' . .
, . . ..
~ . . ' .

. , . . - ' . ' , . ''' ~ ' ' , ~' .
.

_ Ar mp.
- .
2,6-(CH3)2-C6H3 ` ~-thienyl 94,5C
4-Cl-C6H4 2-thienyl ~8.5 C
4-Cl-C6H4 4-C1-C6H4 127.5 C
4-Cl-C6H4 4-CH3-C6H4 112.5C
2-Cl-C6H4 C6H5 123.0C
2-Cl,6-CH3_C6H3 C6H5 114.5C
4-F-C6H4 C6H5 82.0C
3,4-(Cl)2-C6H3 C6 5 115.0C
3-Cl-C6H4 C6H5 ` 92: 0 C
4-Cl-C6H4 4-F-C6H4 1 g. 0C
4-Cl-C6H4 3-CH3-C6H4 121.5C
4-Br-C6H4 C6H5 114.5 C
4-Cl-C6H4 3 OCH3 6 4 121.2C
4-Cl-C6H4 2-Cl-C6H4 139.3 C
4-Cl-C6H4 3-Cl-C6H4 142. 7C
2-Cl,6-CH3-C6H3 4-Cl-C6H4 95.6C
4-Cl-C6H4 2,6-(CH3)2 -C6H3 120. 4 C
3,4 (Cl)2 C6H3 4-Cl-C6H4 - 136.9C
2,5-(Cl)2-C6H3 4-Cl-C6H4 107.0C
, ~ , 2~ 6~(Cl)2~C6H3 4-C1-C6H4 I :~. -C

1~: ' .
; ~ ~ EXAMPLE XV

To a ~tirred solution of 8 parts of ethyl 4-~2,6-dimethyl-phenyl)amirlo7-1-piperidinecarboxylate in 4 parts of pyridine and 25 ~ ~8û part8 of benzene are added drapwise 7. 7 parts of benzeneacetyl chloride in 40 part~ of benzéne. After the addition ig complete, the whole i6 heated to refl~lx and stirred at reflux temperature for 3h.45.
The reaction mixture i6 cooled and filtered. The benzene-pha~e is ~', .~ . ' ~; . -, .
:~: ' - . .
~ ~ ~ -31 -` ~06827~
. "' ' "'`' 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 '_oxybisethaiie, to yield 5 parts of ethyl 4-~-(2, 6-dimethylphenyl)-N-(phenylacetyl)amin~7-l-piperidinecarboxylate; mp, 106C.

EXAMPLE XVI

To a stirred solution of l5 parts of ethyl 4-a4-chlorophenyl)-amin~ piperidinecarboxylate, 5. 4 parts of N, N-diethylethanamine and 160 parts of benzene is added dropwise 11.07 parts of 4-methoxy-io benzeneacetyl chloride at a temperature between 32 to 40C.
After the addition i6 complete, the whole is stirred and refluxed for ¦ 3 hours, The reaction mixture i8 cooled and filtered~ The filtrate is wa6hed successively with water, sodium hydrogen carbonate solution and water, dried, filtered an~ e~,raporated in vacuo. The oily residue ls crystallized from a m~xture of 56 parts of 1, 1 '-oxybisethane and 40 part8 of hexane. The crude solid product is filtered off and recry~tallized from a mixture of benzene and 1,1 '-oxybisethane, yielding 3 parts of ethyl 4-¦N-(4-chlorophenyl)-N~4-me1hoxy-pheny~acety~amino~ _ l _piperidinecarboxylate; mp. 137 C.
.. .

. .
; , .
EXAMPLE X~II
., .
- A mixture of 20 parts of ethyl i_ ~-(2-chlorophenyl)-N-(phenylacetyl)aminoJ~l-piperidinecarboxylate and 300 parts of ^ ~ hydrobromic acid solution 48% is stirred and renuxed for lh. 10.
The hydrobromic acid solution 48% i8 removed in ~racuo and to the re~idue is added successively water and sodium hydroxide solution.
The ~ree base is extracted with trichloromethane. The latter is dried and evaporated. The solid residue is washed with 1, 1 ~-oxybis-ethane and dried, yielding 10.6 parts of N-(2_chlorophenyl)_N_ (4-piperidinyl)benzeneacetamide; mp. 135 . 5 C.
. , . , .

:, . . .

. .
.
-32 _ ___ EXAMPLE XVIII

Following the procedure of Example XVII and using and equivalent amount of an appropriate ethyl 4-LN-aryl-N-(aryl-acetyl)amino~-l-piperidinecarboxylate in place of the ethyl 4-~-(2-chlorophenyl)-N_(phenylacetyl)amino~-l-piperidinecarboxy-late used therein, the following compounds are obtained:

` HN~(N-C-CH2-Ar Ar _ Ar Arl mp.
2-Cl, 6-CH3-C6H3 C6HS 157C
4-F-C6H4 C6H5 96 . 5 C
3~ 4~(Cl)2~c6H3 C6H5 81 C
3-Cl-C6H4 C6H5 1 10. 5C
4-Cl-C6H4 . 4-F-C6H4 109 C
4-Cl-C6H4 3 CH3 C6H4 104.5C
4-Br-C6H4 C6H5 121. 5C
4-Cl-C6H4 2-Cl-C6H4 72. 9-C
4_Cl-C6H4 . 3-Cl-C6H4 64 C
2-Cl, 6-CH3-C6H3 4-Cl-C6H4 . 120. 7C
4-Cl-C6H4 2~ 6-(CH3)2 C6H3147. 3C
3~ 4~(Cl)2~c6H3 4-Cl-C6H4 98. 7C
2, 5-(Cl)2-C6H3 4-Cl-C6H4 125. 6C
:.: 2, 6-(C-~2-C6H3 4-Cl-C6H4 126. 3C
. . ..
.

`~ . - ' . ' ' ` ' .

, .... . . .. . .. . . .
,.. ., . ..... , . , . ... ;. .. . . ~ . . .. . . . .. . .. . . .. .

~068271 `: `

EXAMPLE XIX

A mixture of 5 part~ of ethyl 4-~-(2, 6-dimethylphenyl)-N-(phenylacetyl)amino~-l-piperidinecarboxylate in 6û parts of hydrobromic acid solution 48% iæ warmed until the evolution of carbon dioxide ifi ceased. Heating is continued for 15 minutes at a temperature between 80-120C. The reaction mixture is evaporated.
The solid residue i8 washed successively with methylbenzene and 2-propanone and dried, yielding 4.1 parts of N-(2,6-dimethylphenyl)-N-(4-piperidinyl)benzeneacetamide hydrobromide; mp. 251. 5 C.

:.
. EXAMPLE XX

A mixture of 10 parts of ethyl 4-~-(4-chlorophenyl)-N-(phenylacetyl)amin~7-1-piperidinecarboxylate and 125 parts of glacial acetic acid, previously saturated with gaseous hydrogen bromide, i8 heated for 9h. 45 at 62C, while stirring. The reaction mixture i~ 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 ~odium hydroxide solution and the product - is extracted with trichloromethane. The extract is dried over - eodium sulfate and evaporated. The oily residue is triturated in S6 parts of 1, 1 '-oxybisethane and the solid crude free base i~
filtered off. It ii converted into the hydrochloride salt in tho conventional manner in 1, 1 '-oxybisethane and 2-propanone, yielding 4 parts o N-(4-chlorophenyl)-N-(4-piperidinyl)benzeneacetamide hydrochloride; mp. 206.5C.

! :
.. i~ ~ . ;

i,. .. .
.j .

. .
.
~. .

~ . . . . .

~, .

1068271 .

' EXAMPLE XXI

Following the procedure of Example XX iand using an equivalent amount of an appropriate ethyl 4-~N-aryl-N-(arylacetyl)-amino7-1-piperidinecarboxylate as a starting material, the following compounds are prepared:

N-(2, 6-dimethylphenyl)-N-(4-piperidinyl)-2-thiopheneacetamide;
mp. 128C;

N-(4-chlorophenyl)-N-(4-piperidinyl)-2-thiopheneacetamide hydrochloride;
mp. 201. 5C;

4-chloro-N-(4-chlorophenyl)-N-(4-piperidinyl)-4-benze neacetamide hydrochloride; mp. 222C; and , ` , !
N-(4-chlorophenyl)-4-methyl-N(4-piperidinyl)benzeneacetamide;
mp. 121C.

i5 ` ~ .
` ~ E~AMPLE XXII

,, .
To a Ptirred and refluxing mixture of 48 parts of l-(l-methylethyl)-4-piperidinone, 1 part of 4_methylbenzene_ sulfonic acid and 540 parts of methylbenzene is added dropwise a Rolution of 30 parts of benzen_amine 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-me$hylethyl)-4-piperidinylidene~benzenamine as , a re~idue.

..
To a ~tirred and warn~ed t30-40C) solution of 72 parts of N-r-(l-methylethyl)-4-piperidinyliden~7benzenamine in 480 parts of methanol are added portionwise 20 parts of sodium borchydride. Upon completion, s$irring is con$inued overnight at ~ -i . ` .

. , .
: , .
,... . .

1068~7l . '' ` .
at room temperatur e. The reaction mixture is evaporated and the residue is dissolved in water. The solution is extracted with 4-methyl_2_pentanone. The extract is washed with water and acidified with a diluted }iydrochloric acid solution. The aqueous acid phase i9 aLkalized with a diluted sodium hydroxide solution till pH 9 and the product is extracted with 4-methyl_2_pentanone. The extract is waæhed with water, dried, filtered and evaporated. The residue is distilled ~bp. 135-140C at 0.2 mm. pres9ure) and the distillate is crystallized from petroleumether, yielding 21 parts of 1-(1^
methylethyl)-N-phenyl_4-piperidinamine; mp. 69. 3~C.
., .
:
E~AMPLE 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-chlorophenyl)-N-~-methoxyphenyl)acety~7amino} -1 -piperidine-carboxylate and the whole is stirred and re1uxed hr 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 i-s washed i ~ with 1, 1 ~-oxybisethane, alkalized with sodiurn hydroxide and the free base is extracted with methylbenzene. The latter is dried, filtered a~d evaporated. The residue is dissolved in 1, 1 '-oxybisethane and a~ter crystallization, 10 parts of N-(4-chlorophenyl)-4-methoxy-N-(4-iperidinyl)benzeneacetamide are obtained; mp. 129.5C.
~,~ .
~, EXAMPLE XXI~r `~ To a stirred and warm (40C) solution of 12 parts of ! ~ ~:~ potagsium hydroxide in 200 parts of 2-propanol are added at once 3~ 21 parts of ethyl 4-~N-(4^chlorophenyl)-N-a~-methoxyphenyl)acety~7-3 amino ~-l-piperidinecarboxylate and the whole is stirred and refluxed 1 for 1? hours. The reaction mixt~re is cooled, ~iltered and e~raporated.
` ~- . ' ' ' ' ' ' ~ .
j ~ -36-,. ., .' '.

1068271 ` `
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 trichloromethane. The extract is dried and e~raporated. The residue is crystallized from a mixture of 1, 1 '-oxybisethane and hexanel yielding 7. 8 parts of N-(4-chlorophenyl)-3-methoxy-N-(4-piperidinyl)benzeneacetamide; mp. 85.7C.
: . . ~ -` ~ EXAMPLE XXV
".
A mixture of 52 parts of 2-bromopropane, 19 parts of N-(4-piperidinyl)-3^pyridinamine, 33.3 parts of sodium carbonate, 3 parts of potassium iodide and 720 parts of 4_methyl_2_pentanone i~ ~tirred and re~luxed for 24 hours. The reaction mixture is cooled and ~ltered. The filtrate i8 evaporated. The residue i9 purified by column-chromatography over silicagel using methanol a~
eluent. The pure fractions are collected and the eluent i8 evaporated.
The residue i9 crystallized from 2,2'-oxybispropane, yielding 1.5 '~f parts of N-r-(l-methylethyl)-4-piperidiny~7-3-pyridinamine;
mp. 100. 7C.

'~ . . ' ' ` ` .

EXAMPLE XXVI

~, ~ ~ 20 Following the procedure of Example XXV and using equivalent amounts respectively of an appropriate bromide and of an appropriate 4-tarylamino)-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:
',: ~ ~ ~
o~ :
,..~.. ~
,, : . -, :
` -37- -~:
:~j :
,, ~x~ o ~o . ~
_ , . V V V V V O ~, V
V t~ o ~ .
C o~
' V u~
.
_ '.

. h O . .
~ .
O o~ , .
_~ ~ V
. - .~ ~ _ h V V ~ ~ t) V t) ~ ~ V
o ~ m ; . . ~ , : ~ ~
, . v~ , x 8 8 ~ ~ 8 8 m m, ~ m P h O t.) ~ V
~ ¢ _ . ~r, . ' b U~
~` . l~ V ~ ~ V ~ V ~ ~ V
.., '' _ ' ' .
. ~ ~ O,',' ,' ,.,, ' ;' , ' . ., . - iln 'o . _38-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-bromo-l-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 1,1 '-oxybisethane and treated with activated charcoal. The latter is filtered off and the 1,1 '-oxybisethane i8 evapor at ed again, yielding 2. 9 parts of N-(4-chlorophenyl)- 1 -(2 -propenyl)-4-piperidinamine i mp. 9Q C.

.
EXAMPLE XXVIII
' . ' ' To a warm (about 40C) and stirred mixture of 5 parts of , N-(2,6-dimethylphenyl)-4-piperidinamine, 5 parts of sodium car-lS 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 i-q continued for 40 hours at reflux temperature. The reaction mixturo , i8 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 M-(2,6-dimethylphenyl)-1 -propyl-. 4-piperidinamine; bp. 135C 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 norrnal pressure and at room temperature ~ ~ with 2 parts of palladium-on-charcoal 10%. After the calculated :, ~ . ~ ~ ' '` , ` ' . .
. .. ..
. ~

.

~ 1068Z71 amount of hydrogen is taken up, the catalyst is filtered o~ and the filtrate-is evaporated. The residue is taken up in 4-methyl_2-` pentanone and a small amount of trichloromethane. The whole is was-hed 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-(l-cyclopentyl-4-piperidinyl) -2 -pyrimidinamine; mp. 1 18 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 i8 hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%.
~After the calculated amount of hydrogen i9 taken up, the catalyst is filtered off and the filtrate is e~raporated. The residue is di~solved in trichloromethane. The solution i8 Wa9hea guccessivèly with a diluted sodium hydroxide solution and with water, dried, ` filtered and evaporated, yielding 3 parts of N-~-(l-methylethyl)-4_piperidiny~J-2-pyrimidinamine as a residue.
'.' . , ~
:
EXAMPLE XXXI

To a stirred and refluxing suspension of 2 parts of lithium alu~s~iniumhydride in 120 parts of 1, 1 '-oxybisethane is added dropwise a solution of 13 parts of ethyl 4-~-(2, 6-dimethylphenyl)amino~-1-piperidinecarboxylate in 40 parts of 1,1 '-oxybisethane. A-ter the add~tion is complete, stirring and refluxing i8 continued ~or 20 hours. The reaction mixture is cooled to SC and 7 parts of water are added~ The formed precipitate is filtered off, washed on the filter ~ ` with I, 1 '-oxybisethane and the filtrate is evaporated. The oily residue ;~ is distilled, yielding 5. 8 parts of N-(2, 6-dimethylphenyl)-1-methyl-~_piperidinamine; bp. 90-93C at 0.003 mm. pressure. On standing the di8tillate solidifies, to yield solid N-(2, 6-dimethylphenyl)-1-methyl-4-piperidinamine with a melting point o~ 45G.
'~ : . . ~ .
` ~ _40-` ~ ` ~
~068271 .`
. , , 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 o butanol is added dropwi~e 4 part~ of 2-bromopropane at room temperature. After the addition is complete, the whole i9 stirred and re~luxed for 20 hours~
Then the second portion of 4 parts of 2-bromopropane is added and stirring and refluxing i8 continued for another l9 hours. The reaction mixture i8 cooled, filtered and the filtrate is evaporated. From the oily free bas~, the hydrochloride salt is prepared in the conventional manner in l, l '-oxybisethane and 2-propanone. The precipitated solid ~alt i8 filtered off and crystallized from a mixture of 2-propanone and 2-propanol, yielding 2 parts of N-(4-chlorophenyl)-N-~-(l-methylethyl)-- 4-piperidinyl7benzeneacetamide hydrochloride; mp. 263C.
. ,, .' - ' ' ' ' ..
EXAMPLE XXXIII
.
Following the procedure of Example XXXII and using an equivalent amount of an appropriate bromide and of an appropsiate - N-aryl-N-(4-piperidinyl)arylacetamide as starting materials, the ~o}lowing compounds are prepared in hydrochloride ~alt form:
., : . . ' '.
, .

~`
.
. ~
. :~:
~ ~ .
; ~
::~ .
:

.
. ' , ' . '.,~ . .' ' .' . ~68271 .

. V '~ V ' . .~ o ,~ .~`, .t, U~ u~ ~o U U~ I
~ . o ~ o . o .... ~ o ., , r~ o~ oo ~ `D ~O ~ ~ ~ ~O ~O ~ ~ ~
. I
. ~ o '-. ~ ~ i : . b t) ~.) O O V l ) 1.) : . ;~
., tq ; .
: _ ~ , ' j . _~
., ¢ _.' ~
~) h .. ~
: l ¢ ~ O
. ~_. ~ .
vy b ~ ~ ) ~ v V ~ ~.) ~ t.) U
~ ~-¢, _ . ~ '. 0~
' ~ ¢ Pi~
',' . ~ V o ~ V ~ j .:
. t~ V t.) . .
. , ~, ~ ' .' ' ' I.
.. .
P

~, : `~ V V V O V O ~ ~ V ~ - t) , :i ~ : , , ,. , , , , , . . ~S` ~ I
s, ~,~ ~~ ~ ~ ~ ~ ~ ~ ~ ~, ., ~ . ~ ~ ~ C`~
t~ O V t~ t) V V O ~ I
,, : . ' .~. ~:. . - . . ~ -.~ ~ _ , , .

.j ~,: : ,: , :; :
:, :

'1:

~ 1 , : .
~' ~`
:." : ,U~ o , ~ . : . ... . :. .. . . .

10682'7~ ;
_ .
V V V V V
. o o o o o . U~
P~ . . . . . o ~ . _. ~ ~ ~
. . _ . ' . .
h O _l _~ _ _l _ _ , ~ V O V V V V ' . X 1 ~ .
. . _ .
. . ~.
. V~ '.
l 1~
: _, U) ~) It-) ~- ~ '~
: . h ., . ¢ ~V~V~ V~ .' ,' . . .
l . . ,.
,, pj~
" . `O ~O ~ ~ `O ~O
:' ., ¢ O ~ O t.) V, ~': , ' _ ~ yt~ V~
~, .~ . ~1~ ' ..
. ~ ~ V~
;~ ; ` ~ ~ ~ ~ b I 1~

.`. -.. ~
, .
., ~ ~ ~
:
~:
. . , n , ' .
~ _43- `
.
.
., . : . ..

` ` 1~68271 EXAMPLE XXXIV

To a stirred and warm (40C) mixture of 5 parts of .N-(4-chlorophenyl)-N-(4-piperidinyl)benzeneacetamide, 5 parts of sodium carbonate, a few crystals of potassium iodide and 200 parts of n,butanol is added 3. 75 parts of bromocyclopentane and the whole i8 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, iltered and the filtrate i8 evaporated. The oily residue solidifies ~ on triturating is~ 1, l~-oxybisethane. The solid product is filtered off and crystallized from 1, 1 '-oxybisethane, yielding 1.1 parts of N -(4-chlorophenyl)-N -(I _cyclopentyl -4-piperidinyl)benzeneacetamide;
mp. 139.5C.

EXAMPLE XXXV

,l 15 Following the procedure of Exarnple XXXI~ and using . e~uivalent amounts respectively of an appropriate bromide and of an appropriate N-aryl-N-(4-piperidinyl)arylacetamide as starting materials, the following compounds are obtained:
, ., L-l~( I -C-CH2-Ar , . Ar ,, ~ ... ~:
, .' I 1 ' ~ ~ L Ar ~ Ar mp.
; ~ (CH3)2-C;H-4-F-C6H4 C6H5 .108. 5 C
(CH3)2-CH- 4-Cl-C6H4 4-Cl-C6H4 106. 5C
. ~ .__~____________ _________________ _.. ____________ ________ ~i ::: :`: ~, ~, ~:: :
--44 _ .. . . .
~. . ~ , . .. .

.
-.; , ` ' ' ~ - - - ; . ~ . .

:~068271 .
. .

L ¦ Ar ¦ Ar ¦ mp- ¦
(cH3)2-cH- 4-Br-C6H4 C6H5 97- C
(CH3)2 4_C1_C6H4 2-C1 _C6H4 143. 2C
(CH3)2_CH_ 4_C1_C6H4 3_0CH3_C6H4 96. 4C
(CH3)2 CH~ - 4-C1-C6H4 3 C1 C6H4 61. 6C
. (CH3)2_CH_ 2-C1, 6-CH3-C6H3 4_C1_C6H4 94. 2C
tCH3)2~CH~ 4_C1_C6H4 2, 6-(CH3)2-C6H' 126. 6C
(CH3)2 CH 2, 5-(C1)2-C6H3 i C1 C6H4 102.5C
(CH3)2~CH~ 2, 6-(C1)2-C6H3 4 C1 C6H4 129.1 C
s (CH3)2-CH- 2-Cl-C6H4 C6H5 87. 5C . .
4 C1 C6H4 4-C1-C6H4 133. 1 C
~ C 4_C1_C6H4 2-C1-C6H4 128. 6C
;~ ~ 4 C1 C6H4 3~CH3~C6H4 157. 5C~i D- 4-Cl-C6H4 3-CH3-C6H4 155C
4-Cl-C6H4 4-F-C6H4 143. S - C

, . . ..
~s , ~ ! ~

.`1 : ~ '` . ,` - ..

;

1068'~7~ `

EXAMPLE XXXVI
, To a stirred and refluxing mixture of 5 parts of N-t4-chlorophenyl)-N-(4-piperidinyl)benzeneacetamide, 5 parts of sodium hydrogen carbonate and 200 parts of benzene are added portionwise

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-~-(cyclopropylmethyl)-4-piperidiny~7benzeneacetamide hydrochloride; mp. 224C.
-EXAMPLE XXXVM

To a stirred solution of 5 parts of N-(4-chlorophenyl)-N-(4-piperidinyl)benzeneacetamide, 3. 8 parts of N, N-diethylethan_ amine in 200 parts of benzene are added portionwise 5 parts of ' 3-bromo-1-propene. After the addition is complete, the whole $ 20 i~ heated for 21 hours at a temperature between 50-60C. The i 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 re~idue i8 converted into the hydrochloride salt in 1,1 '-oxybisethane and 2-propanone, yielding 4 parts of N-(4- chlorophenyl)-N-~-(2-propenyl)-4-piperidiny~7benzeneacetamide hydrochloride;
, mpD 225.5C.
,................................................................ .

. . ' . i . . .
. ~; . - .
- . . .

~' ' "'' ' .'`' ' ' ' '.
. ~ . ...

~ . 106&271: `
.

- EXAMPLE XXXVIII

Following the procedure of Example XXXVII and using an equivalent amount of a~n appropriate N-aryl-N-(4-piperidinyl)-arylacetamide in place of the N-(4-chlorophenyl)-N-(4-piperidinyl)-benzeneacetamide used therein, the following compounds are prepared: `
, N-(2, 6-dimethylphenyl)-N-~-(2-propenyl)-4-piperidiny~7-2-thiopheneacetamide hydrochloride; mp. 203. 5 C; and N-(2, 6-dimethylphenyl)-N-[-(2-propenyl)-4-piperidiny~7benzene-, 10 acetamide hydrochloride; mp. 214C.
' '. .
'' ' ' - EXAMPLE XXXIX

1 To a warm suspension of 5 parts of N-(4-chlorophenyl)_ 3, N~piperidinyl)benzeneacetamide, 5 parts of sodium carbonate, a few crystals of potassium iodide in 200 parts of n. butanol i9 added ¦ 15 4 parts of 2-chloro-2-methylpropane at a temperature of 30-40C.
~ ~ The whole i,s stirred and refluxed for 140 hour~ during which time, ¦ 35 parts of 2-chloro-2-methylpropane are added in portions as follows:
after a reflux-time of 15 hQurs, 4 parts of 2-chloro-2-methylpropane is added, after 8 hours, 10 parts,after 16 hours, 11 parts and finally Y 20 after 47 hours, 10 parts. The reaction mixture i3 cooled, filterod and the filtrate is evaporated. The semi-solid residue is dissolved in a :mixture of methylbenzene, dimethoxyethane and 1, 1 '-oxybis-ethane. The solution i9 filtered from some impurities and the filtrate iB evaporated again. From the oily residue, the hydrochloride salt is prepared in the conventional manner in 1, l '-oxybisethane, yielding, - -after recsystallizàtion of the crude solid salt from 2-propanone, 0. 9 parts of N-(4-chlorophenyl)-N~ dimethylethyl) -4-piperidinyi7 benzeneacetamide hydrochloride; mp. 221C.

. ~, . ~ . . .
,i -:.

` EXAMPLE XL ` `
. , , ^ '.
A mixture of 4 parts of iodoethane, 5 parts of N-(2, 6-di,methylphenyl)-N_(4-piperidinyl)benzeneacetamideJ 5 parts of sodium carbonate, a few crystals of potassium iodide in 200 parts of benzene is stirred and refll~xed for 23 hours. The reaction mixture is filtered hot and the filtrate is e~raporated in : vacuo. The solid residue is crystallized from 1, 1 '-oxybisethaneJ
yielding 2 parts of N-(4-chlorophenyl)-N-(l-eth~1-4-piperidinyl)-benzeneacetamide; mp. 86.5C.

. 10 EXAMPLE XLI
, . ' Following the procedure of Example ~L and using an . equivalent amount of an appropriate N-aryl-N-(4-piperidinyl)-, arylacetamide in place of the N-(2, 6-dimethylphenyl)-N-(4-piperidinyl)benzeneacetamide usedtherein, the following compounds are prepared:

. 2-chloro~N-(4-chlorophenyl)-N-(1 -ethyl-4-piperidinyl)benzeneacetamide hydrochloride; mp. 234.6C;

. ~ . N-(4-chlorophenyl)-N-(l-ethyl-4-piperidinyl)-3-methylbenzene-acetamide; mp. 78.5C;
'.,' ~: ~ 20 N-(4-chlorophenyl)-N-(l-ethyl-4-piperidinyl)-4~methylbenzene-., ~
:'t ~ ' acetamide; mp. 50 G; and . N-(4-chlorophenyl)-N-(l-ethyl-4-piperidinyl)-4-~uorobenzeneacetamide;
. mp. 62. 3C.
. ~
.. ,.~ - -. ~

;
:~ :~
. :~
.

1 ~
~. .. ' . .
: -48-, "' ' ' ' "

. - . . . . .

1068~71 - EXAMPLE XLII
. ....
` To a stirred and refluxing mixture of 5 parts of 4-chloro-N-(4-chlorophenyl)-N-(4-piperidinyl)benzeneacetamide, 5 parts of ~odium carbonate, 0.4 parts of potassium iodide and 200 parts of butanol is added 4. 7 parts of l-iodopropane and the whole is stirred and renuxed for ~2 hours. Then a second portion of 4. 5 parts of l-iodopropane is added and stirring and refluxing is continued for 27h. 30. The reaction mixture i8 cooled, filtered and the filtrate is evaporated. The semi-solia residue i8 dissolved in methylbenzene.
The solution is filtered from some impurities and the filtrate is evaporated again. The residue is crystallized from 1, 1 ' -oxybis -ethane at -10C, yielding 0. 9 parts of 4-chloro-N-(4-chlorophenyl)-N-(l-propyl-4-piperidinyl)benzeneacetamide; mp. 118.6C.
.
. . . , . EXAMPLE XLIIl .

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 ase added portionwise 4 parts of l-iodopropane and the whole is stirred and refluxed for 47 hours. Then the second portion of 4 parts of I-iodopropane is added and stirring and renuxing i8 continued for another 20h. 20. The reaction mixture is cooled and filtered. The filtrate i9 washed with water, dried and evaporated in vacuo. From the oily free base, the hydrochloride salt is prepared in the conventional manner in 1, 1 '-oxybisethane. The precipitated ~olid salt is filtered off and dried, yielding 3. 5 parts of N-(4-chloro-2S phenyl)-N-(l-propyl-4-piperidinyl)benzeneacetamide hydrochloride;
" ~ n~p. 233.5C.

. ~
~ ~ _49_ .
:~
' . ', ~ ~ ' - ' ' : ,. . . .
. ' , .
. ' ' , ' . ' . .
. ' ~ -- : .,: ... . .

1068Z7i EXAMPLE XLIV
.' '' `
Following the procèdure of Example XLIII and using an equivalent amount respectively of an approp~iate iodoalkane and of an appropriate N-aryl-N-(4-piperidinyl)arylacetamide in place of the l-iodopropane and the N-t4-chlorophenyl)-N-(4-piperidinyl)benzeneacetamide used therein, the following compounds are obtained: ' , N-(2, 6-dimethylphenyl)-N~ ethyl-4-piperidinyl)-2-thiophene-- acetamide hydrochloride; mp. 258C;

N-(4-chlorophenylj-N-(l-ethyl-4-piperidinyl)-2-thiopheneacet-amide hydrochloride; mp. 220.5C;
,' , , ' , - ' .
N-(4-chlorophenyl)-N-(l -ethyl-4-piperidinyl)benzeneacetamide hydrochloride; ~np. 215 C;
:: .
., ,. .
4~chloro-N-(4-chloropheny})-N-(l -ethyl-4-piperidinyl)benzene-acetamide hydrochloride; mp. 224C; and .
N-(4-chlorophenyl)-N-(l -propyl-4-piperidinyl)-2-thiophene-~ acetamide; mp. 241C.
,~ , ~ .
,~.
` ~ ~ - EXAMPLE XLV
,." ., A mixture of 4. 5 parts of N-(l-cyclopentyl-4-piperidinyl)-i!O~ 2-pyrimidinamine, 3.4 parts of 3 methylbenzeneacetyl chloride, ; 2 parts of sodium carbonate and 180 part~ of dimethylbenzene i9 tirred and refluxed for 17 hours. Another 9 parti~ of 3-methyl_ benz~neacetyl chloride is added dropwise. Upon completion, stirring j.. ~ i8 continued for 67 hours at reflux temperature.- The reaction , . ~

- ~ ~
i ~ -50-'.`, ~ - ' . -:
, "

.
''' _ ' ' .

, , ~, . . .
-. . .

106827~ `
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 i8 extracted twice with trichloromethane.
The combined extracts are dried, filtered and evaporated, The residue is con-terted into the ethanedioate salt in 2-propanol. The salt i8 filtered off and crystallized t~iLce: first rom ethanol and then from methanol, yielding 1 part of N-(l-cyclopentyl-4-piperidinyl)-3-methyl_N-(2-pyrimidinyl)benzeneacetamide ethane-, dioate; mp. 204.1C.
~I . . .

. , .
EXAMPLE XLVI
. , .
' Following the procedure of Example XLV and using equivalent j ` 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:
-L-l~(~l-C-CH2-Ar j Ar ~, , , L Ar ~ Arl base or salt form mp.
.
- 3-pyridinyl C6H5 (E)-2-butenedioate 219.

- 3-pyridinyl 3-CH3-C6H4 (E~-2-butenedioate 250. 3C
D- 2-pyric7inyl3-Cl-C6H~ (COOH)2 205. 9 C
D- 2_pyridinyl3-CH3-C~;H4 base . 107. 8~C

___________ ~_____________ ____________ ________________ _______ . .

`! ` `` ` -.-.
.
`- : . . . . :
` . , 106~Z71 `
.

L Ar Arl salt form mp.
D- 2-pyri-linyl 4-Cl-C6H4 base 119.2C
iD- 2-pyridinyl 2-thienyl base 129.4 C
D' 2-pyridinyl C6H5 base 108.8C
- 2 -pyrimidinyl C6H5 `(COOH~ 223.5 C
(CH3)2-CH- 3-pyridinyl C6H5 - base 129.4 C
(CH3)2-CH- 3-pyridinyl 3-Cl-C6H4 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-pyridinyl3 - CH3-C6H4 bas e 100 C
(CH3)2 -CH_ 2-pyridinyl 3-Cl-C6H4 base 102.6 C
(CH3)2-CH- 2-pyridinyl C6H5 base 72.1 C
(CH3)2-CH- 2-pyridinyl 4-Cl-C6H4 base 83.3-C
(CH3)2 CH 2-pyridinyl 3 CH3 C6H4(COOH)2 190.6C
(CH3)2-CH- 2 -pyrid~nyl Z-thienyl(COOH)2 196.1 C
(CH3)2-CH- 2-pyrimidinyl 4-Cl-C6H4 (CooH~2 19S.7- C

.

, ~ ~ EXAMPLE XLVII
~1 .
-3 ~ A m~xture of 5 parts of methyl 1-(1-methylethyl)-4-phenylamino)-4-piperidinecarboxylate, 24 parts of 4-chloro-b0nzeneacetyl chloride, 4 parts of sodium car~onate and 180 ,~ , .

`.; ~ ~ ` , ' ' ~ ~ ~ -52-`~` : -~j; : ' ' ' , . ~ . , .

., .
,.~ . .
.:

`` 1~8271 . .'' parts of dimethylbenzene is stirred and reflwced 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 allcalized with a diluted sodium hydroxide solution.
The product is extracted with 4-methyl_2_pentanone, The extract i~ washed with water, dried, filtered and e~aporated. The residue i8 converted into the ethanedioate salt in 2-propanol. The salt i8 filtered off and crystallized from a mixture of 2-propanol and 2,2'-oxybispropane, yielding 5 parts (48%) of methyl 4-LN-(4-chlorophenyl)acetyl-N-phenylamino7-1-(1 _methylethyl?_4_ piperidinecarboxylate ethanedioate; mp. 154.2C.
.' ' . -- EXAMP~E XLVIII
, ,' ' Following the procedure of Example XL~tII and using equivalent amounts respectively of an appropriate 4-arylamino-4-piperidinecarboxylate and of an appropriate arylacetyl chloride a8 ~tarting materials, the following compounds aro obtained in free base form or in the form of an acid addition salt after treatment with the appropriate acid:

CH2-Ar ... .
~, ~ _ R base or mp.

(CH3)2-CH- 3-CH3-C6H4C2H5 (COOH)2 198. 4 C

i ~ (CH3)2-cH- _ C6H5 C2H5 . dioate 168. 5C
-, ____________ ___________ __________.__ ___________ ___________ ~7:

. I :
~`.',' ;' '' ' ' , .
.... ~ . .
53_ ... . .
3 ` -.
`~: j 10f~i8271 (CH3)2-GH- 2-thienyl Ci H5 (COOH)2 156. 8C
(CH3)2-cH- 4-Cl-C6H4 C2H$ HCl 191. 5C
(CH3)2-cH- 3-CH3-C6H4 CH3 (COOH)2 1 70C
(CH3)2-cH- 3-Cl-C6H5 CH3 (COOH)2 152. 2 C
(CH3)2-CH- C6H5 - CH3 (COOH)z 165. 5C
(CH3)2-CH- 2_thienyl CH3 (COOH)2 173. 6 C
[ ~ 4-Cl-C6H4 C2H5 (E)_2 -butenedioate 195. 6 C
D~ C6H5 C2H5 (E)-2-butenedioate 203. 3C
D 3-Cl-C6H4 C2H5 (E)-2-butenedioate 20l. 8C

i 3 3 CH3 C6H4 C2H5 (E)-2-butenedioate 188.1 C
C6H5 CH3 (COOH?2 197. 2C
D' 2-thienyl CH3 (COOH)2 166. 4C
` D~ 3-Cl-C6H4 CH3 base 94 C
. 3 CH3 C6 4 CEI3 (COOH);~ 19. S-C

.

,' EXAMPLE I L
' - To a stirred mixture of 4. 4 parts of 1-(1 ^methylethyl)-N_ phenyl-4-piperidinamine, 5. 3 paxts of sodium carbonate and 180 partQ
of benzene are added dropwise 5 parts of bènzeneacetyl chloride.
Upon completion, stirring is continued overnight at reflux. The reaction mixture i8 cooled, washed successively with water, a oodi~um hydrogen carbonate solution and again with water, dried, :' ' .
~ -54-; ~" .' - ' ' ' .
, . . .
~ ': . ' ' ' _ . . . . . . . .. . .
.
. . . ~ .... -106~271 : " ', .

iltered and evàporated. 'rhe residue is convèrted into the hydrochloride ~alt in-2, 21-oxybispropane and 2-propanol. The formed salt is fil~ered off and crystallized from a mixture of 2-propanol and 2, 2'-oxybis- -propane, yielding 2.5 parts of N-~-(l-metl~ylethyl)-4-piperidiny~7_ S N' phenylbenzeneacetamide hydrochloride; n~p. 184.4C.

EXl~MPLE L

E`ollowing the procedure of Example IL an~ using equivalent amounts respectively of an appropriate N-aryl-4-pipexdinarnine and of an appropriate arylacetyl chloride as starting matcrials, the following - compounds are obtained in base form or in the form of an acid addition 8alt after treatment with the appropriate acid:
.

CH _Ar r . , i-- ~
L Ar Ar base or salt forn~ mp.
. . . ..
~C~3)2-cH- C6H5 3 ~;H3 C6H4 HCl 173. 6 (CH3)2-CH- C6H5 3-C1-C6H4 HCl 204. 8' (CH3)2-CH- C6H5 2-thienyl (E)-2-butenedioate 168.1 ' CH3 2, 6-(CH3)2-C6H3 C6 5 base 95. 5C
CH3 4-Cl-C6H4 C6H5 base 1 15 C
C2H5 4-Cl-C6H4 3 C6H4 base 90. 7C
nC3 7 2, 6-(CH3)2-C6H3 2-thienyl (COOH)2 153C
__________ _______________ ____________ _________________ ______.
' . _ .. _ , .: . _ _ . . . _ ... .... _ .. . .. .. . ... .... . . . . .

- ' , ' ' .

~068271 Ar Arl base or salt form mp.
.
3 72, 6-(cH3)2-c6H3 C6H5 (COOH)2 161 C
CH2 =CH-CH2 4-Cl-C6H4 2 -thienyl HCl 227. 5 C
i D- C6H5 4-Cl-C6H4 base 125. 1 C
D- C6H5 3 CH3 C6H4 (E)-2-butenedioate 161. 3C
D- C6H5 2 -thienyl base 119 C
3 C6H5 3-Cl-C6H4 base ` 121. 8C
3 C6H5 C6H5 base ~ 139. 8C
D- 3-pyridinyl 4-Cl-C6H4 base 149. 9 C
D' 3-pyridinyl 3-Cl-C6H4 2 HCl. 1 /2H20 236. 6 C
D- 3-pyridinyl 2 -thienyl base 159. 8 C
@)- C6H5 4-Cl-C6H4 HCl 265. 8C
C6H5 3~ Cl-C6~ HCl Z 5 5 . 4 C

: .
., ' ' '.
E~AMPLE LI

A ~uspension of 1.25 parts of sodium amide in 56 parts of benzene is ~tirred under nitrogen atmosphere and warmed to a temperature of 40-C. Then there is added dropwise a solution of 6 parts of N-(4-chlorophenyl)-1-(1-methylethyl)-4-piperidinamine in 56 parts of benzene. Upon completion, the whole is stirred and renuxed for 16h. 45. The mixture is cooled to 25C and there is added a mixture of 7. 8 parts of 3, 4-dichlorobenzeneacetyl chloride in 88 parts of benzene. After stirring and rzflu~ing for 2 additional hours, the reaction mixture is cooled and 80 parts of water are added.
The whole i9 acidified with a diluted hydrochloric acid sol~ion. The . ' , .
~' . ' ' ' -', ' ' , ' ' . ' .

,.
.. . -: ~
, . .

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 i8 cooled o~rernight at -10C, 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 -10C, yielding 2.2 partq of 3,4-dichloro-N-(4-chlorophenyl)-N-r-(l-methylethyl)-4-piperidin~benzeneacetamide; mp. 101.7C.

EXAMPLE LII
. . .
Following the procedure of Example LI and using equivalent amounts respecti~rely 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 sa1t after treatment with the appropriate acid:

4-bromo-N-(4-chlorophenyl)-N- /i~-(l -methylethyl~_4~piperidiny~7-benzeneacetamide; mp. 1 18. 1 C;

4-chloro-N-~2, 6-dimethylphenyl)-N-C-(l-methylethyl)-4_piperidiny~7_ benzeneacetamido hydrochloride; mp. 268.2C; and N-(4-chlorophenyl)-4-(1 -methylethyl)-N-~-(l -methylethyl)-4-piperidiny~7~enzeneacetamide; mp. 104.9C.
' ' . .

EXAMPLE LIII

5 Parts of 4-chl~ro-N-(4-chlorophenyl)-N-~-(l-methyl-ethyl)-4-piperidiny~7benzeneacetamide are dissolved in a mixture of 60 parts of 1, l'-oxybisethane and 16 parts of 2-propanone. The .
resulting solution is acidified with an excess of 2-propanol previously saturated with gaseous hydrogen chloride. The precipitated salt is filtered off and dried, yielding 7. 5 parts of 4-chloro-N-(4-chlorophenyl)-N-~l-(l-methyiethyl)-4-piperidinyl~benzeneacetamide hydrochloride;
mp. 266. 6C.

EXAMPLE LIV

From 6 parts of N-~-(l-methylethyl)-4-piperidiny~7-N_ phenyl-2-thiopheneacetamide (E)-2-butenedioate, the free base is liberated in the con~rentional manner with a diluted sodium hydroxide solution. The prbduct i8 extracted with trichloromethane. The extract is washed with water, dried, filtered and evaporated. The residue i9 converted into the ethanedioate salt in 2-propanol. The salt is filtered off and dried, yielding 3. 2 parts of N-~-(l-m~thylethyl)-4-piperidinyl7-N-phenyl~2-thiopheneacetamide ethanedioate; mp. 167.4C.

- From an aqueous solution of 2. 8 parts of N-(2, 6-dimethyl-phenyl)-N-(l-propyl-4-piperidinyl)-2-thiopheneacetamide dihydrochloride, tho free base is liberated by alkalization with sodium hydrogen carbonate solution. The ~ree base i8 extracted with 1, 1 '~QYybis-ethane. The extract is dried and evaporated. The oily residue is dissol-~red in 56 parts of hexane and after cooling to -10C, the solid free base i8 precipitated. It i8 filtered off and dried, yielding 1. 6 parts of N-(2, 6 -dimethylphenyl)-N-(l -propyl-4-piperidinyl)-2-thiophene_ acetan~ide; mp. 62. 5C.

_58-~ ' . , ' - .

.

EXAMPLE LVI_ From 3.9 parts of N ^(l -cyclopentyl-4-piperidinyl) -3 -methyl-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 i9 washed with water, dried, filtered and evaporated. The residue i9 converted into the ethanedioate salt in ethanol. The salt i~ filtered off and crystallized from a mixture of ethanol and 2,2'-oxybispropane, yield~ng 3 parts of N-(l-cyclopentyl-4-piperidinyl)-3-methyl-N-(3-pyridinyl)benzeneacetamide ethanedioate; mp. 192.6C.

EXAMPLE LVII

A mixture of S0 parts of 4-(phenylamino)-1-(phenylmethyl)-4-piperidinecarboxamide and 600 part~ of a concentrated hydrochloric acid ~olution i~ refluxed for 16 hour~. After cooling the reaction mixture i~ concentrated under diminished pres~ure to a volume of 400 parts, whereupon a precipitate is formed. It i8 filtered off, washed with water and 2-propanone and dried, yiel~ling 43 parts of 4-(phenylamino)-1-(phenylmethyl)-4-piperidinecarboxylic acid di}~ydro-chloride; mp. 261 -263 G (dec. ) .

A mixturo of 19 parts o 4-(phenylamino)-1 -(ph~nylmethyl)-4-pipèridinecarboxylic acid dihydrochloride, 14.4 parts of sulfuric acid and 64 parts of ethanol is stirred and refluxed for 16 hours. The olvent i8 decanted. The residue is dissolved in water. The aqueous ~ .
- , ..

' - . . - . .. . . . .. . ... .. . . .... . .. . . . .

` 1068Z7i 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 evapo-rated. The oily residue is dissolved in 200 parts of 2,2'-oxybispropane and ga~eous hydrogen chloride is introduced into the solution. The precipitated hydrochloride i~ filtered off, washed with 2-propanol, filtered off again and dried, yielding 11.5 parts of ethyl 4-{-phen~l-amino)-l-(phenylmethyl)-4-piperidinecarboxylate dihydrochloride;
mp 212-214.4C.

To a stisred and refluxing solùtion of 101.4 parts of ethyl 4-(phenylamino)-1-(phenylmethyl)-4-piperidinecarboxylate in 640 parts of dry benzene i~ added dropwise a solution of 172 part~ 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 80C. The reaction mixture i~ cooled, poured onto ice-water, alkalized with sodium hydroxide ~olution and the product is e~tracted with benzene.
The extract is wa~hed twice with water, dried, filtered and evaporated.
The residue i~ converted into the hydrochloride salt in 2-propanol and I,1 '-oxybisethane. The salt is filtered off, boiled in 2-propanol and after cooling, the product is filtered off. It i9 boiled once more in acetonitrile and the ~alt is fiitered off again after ccoling. The free base i9 liberated in the conventional manner After extraction with 1,1 '-oxybisethane, the latter is washed with water, dried and eva-porated, yielding 56.6 partY of 4-(phenylamino)-1 -(phenylmethyl)_4_ piperidinemethanol as an oily re~idue.
.
l'o a solution of 32 parts of 4-(phenyla~ino)-1-(phenylmethyl)-4-piperidinemethanol in 90 -parts of benzene are added 0.2 part~ of N,N,N-triethylbenzenemethanaminium chloride and 150 parts of a sodium hydroxide ~olution 60%. A~ter stirring vigourously, there are .

~06827~ `

added dropwise 10. 9 parts of dimethyl sulfate at a temperature below 30C. 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 lh. 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-(phenylmethyl3-4-piperidinamine as a residue.

A m;xture of 10 part~ of 4-(methoxymethyl)-N-phenyl-l-(phe-nylmethyl)-4-piperidinamine and 200 parts of acetic acid i8 hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen i8 taken up, the catalyst is filtered off and the filtrate is evaporated. The oily residue is diseolved ~n water, cooled and alkalized with ammonium hydroxide. The product is extracted with trichloromethane. The extract Z0 i~ washed with water, dried, filtered and evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) saturated with gaseous ammonia, as eluent. The pure fractions are collected and the eluent is ovaporated, yielding 4. 5 parts of 4_(methoxymethyl)_N_ phenyl~4-piperidinamine as an oily residue.
.
A m~ture of 10 parts of 2_bromopropane, 9 parts of 4-~methoxymethyl)-N^phenyl-4-piperidinamine, 4. 9 part3 of N, N-diethyl-othanamine and 72 parts of N, N-dimethylacetamide i~ stirred and re-fluxed for 10.25 hours. After cooling, the formed N,N-diethylethan-30 - amine hydrobromide is filtered off and the filtrate is diluted with water.
The product is extracted with methylbenzene. The extract i6 washed t}~oroughly with water, dried, $1tered and evaporated. The residue -6 1 _ i8 purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10) a~ eluent. The pure fractions are collected and the eluent is evaporated, -yielding S. 7 parts (42. 6%) of 4-(methoxymethyl)-1 -tl -methylethyl)-N-phenyl-4-piperidinamine as an oily residue.

To a stirred mixture of 5. 5 parts of 4-(methoxymethyl)-1-(l-methylethyl)-N-phenyl-4-piperidinamine in 56 parts of benzene i~ added dropwise a solution of 13. 8 ~parts of benzeneacetyl chloride in 45 part~ of benzone at 26-.32C. Upon completion, stirring i8 con-tinued first for one hour at 26-32C and further for 3. 60 hours at 38-55C. After cooling, the precipitated product is filtered off and con-~rerted into the hydrochloride salt in a mixture of 2-propanol and 2-propanone (5:1 by volume). The salt i8 filtered off and dissolved in absolute ethanol. After standing for 72 hours at room temperature, the precipitated product i8 filtered off, washed with a smalI amount of 2-propanone and dried, yielding 1. 05 parts of N-~-(methoxymethyl)-l -(l -methylethyl)-4-piperi iny 7-N-phenylbenzeneacetamide hydro-chloride; mp. 249. 1 C .

EXAMPLE LVIII
-By repeating the proceduro 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 aro prepared from tho appropriate starting materials:

4-~methoxymethyl)-N-(3-methylphenyl)-1-(phenylmethyl)-4-piperidin-amine;

4-~methoxymethyl)-N-(4-methylphenyl)-1-(phenylmethyl)-4-piperidin-amine, 4-~methoxymethyl)-N-(2-methylphenyl)-1-(phenylmethyl)-4-piperidin-amine;
, .: ~:
:- ' : ' , ~ -62_ ' ' ' ' , . . ; . : ~ , - -- . . . . . . . . . .. . . .

N-(4-fluorophenyl)-4-(methoxymethyl) -1 -(phenylmethyl) -4-piperidin-amine;

, 4-(ethoxymethyl)-N-phenyl-l-(phenylmethyl)-4-piperidinamine; and 4-(ethoxymethyl)-N-(4-nuorophenyl)-1 -(phenylmethyl)_4-piperidin-amine, .

EXAMPLE LIX

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-~4-(methoxymethyl) -1 -(phenylmethyl) -4-piperidinyl7-N-phenyl-benzeneacetamide;

, N-~-(methoxymothyl)-l -(phenylmethyl)-4-piperidiny~7-N-(3-mothyl-lS phenyl)benzenoacetamide;

N-~E-(mothoxymethyl)- 1 -(phenylmethyl)-4-piperidiny~J-N-(4-methyl-phenyl)benzeneacetamide;

N-~i-(methoxymothyl)-l -(phenylmethyl)-4-piporidiny.~7-N-(2 -mothyl-phenyl)benzeneacetamide;

N-(4-fluorophenyl)-N-~4-(methoxymethyl)-1-(phenylrnethyl)-4-piperi-diny~7benzeneacetamide;

N~ (ethoxymethyl)~ phenylmethyl)-4-piperidiny~-N-phenylbenzene-acetamide;

`

; ~ `. ^63-. . .

~06S271 N-~-(ethoxymethyl)- 1 -(phenylmethyl)-4-piperidinyl7_N(4_fluorophenyl)-benzeneacetamide;

N-~-(methoxymethyl)- 1 -(phenylmethyl)-4-piperidinyl~;7-N-phenyl-4-methylbenzeneacetamide;

N-r-(methoxymethyl)-l-(phenylmethyl)-4-piperidinyl7-N-phenyl-4-methoxybenzeneacetamide; and N-~-(methoxymethyl) - l -(phenylmethyl) -4-piperidinya7-N-phenyl-2 -thiopheneacetamide .

EXAMPLE LX

Following the procedure of step 5 of Example LVII the following compowds are prepared ~tarting from the appropriate phenylmethyl ~ub~tituted precursor~:

N-~4-(methoxymethyl) -4 -piperidinya7-N-phonylbenzeneacetamide;

N-,!-4 -(methoxymethyl) -4 -piperidiny~7-N-(3 -methylphenyl)bensene -ac-tamide;

N-~-(methoxymethyl) -4-piperidinyl7-N-(4-methylphenyl)benzene-acetamide;

N-r-(methoxymethyl)-4-piperidiny~7-N-(2-methylphenyl)benzeneacet-amide;

20 : N-(4-fluorophenyl)-N-~-(methoxymethyl)-4-piperidinyl7benzeneacet-amide;

N-~-(ethoxymethyl)-4-piperidiny~7-N-phenylbenzeneacetamide;

. : . ' ' 1068Z7~.

N-~4-(ethoxymethyl)-4-piperidiny~7-N-(4-fluorophenyl)benzenezcetamide;

N-[4-(methoxymethyl)-4-piperidiny~7-N-phenyl-4-methylbenzene-acetamide:

N-~-(methoxymethyl) -4-piperidiny.~7-N-phenyl-4-methoxybenzene-acetamide; and N-~F-(methoxymethyl) -4-piperidiny~7-N-phenyl-2 -thiopheneacetamide.

EXAMPLE LXI

To a ~tirred mixture of 7. 5 parts of N-(4-chlorophenyl)-l -(l -methylethyl)-4-piperidinamine and 8 0 parts of 4-methyl-2 -pentanone are added dropwise 9 parts of ~-(2-chloro-2-oxoethyl)-phenyl7 ethyl carbonate. Upon completion, the whole is heated to reflux and stirring i~ continued for one hour at reflux temperature.
After cooling, the precipitated product i~ filtered of~ 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 i~ evaporated, yielding 5. 5 part~ of t4-~-~ (4-chlorophenyl)-~ methrlethyl)-4-piperidiny~amino ~-2-oxoethy~7phenyl }
;~ ~ ethyl carbonate as an oily residue.

-~ ~ .
. ' ' ' ~ :
, ,, , . , .;

A mixture of 5. 5 parts of l4 ~ ~ (4-chl,orophenyl)~-(1-methylethyl)-4-piperidinyl7amino~-2-oxoethy~7phenyl ~ ethyl carbonate and 50 parts of a sodium hydroxide solution 10;~ is stirred for 90 minutes at 45C. 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 i8 dried, filtered and evaporated. The oily residue is purified by column-chromato-graphy over silica gel using a mixture of trichloromethane and methanol (80:20 by volume) as eluent. The pure fractions are col-lected and the eluent is 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 60C, yielding 1. 9 parts of N-(4-chlorophenyl)-4-hydroxy-N-L~-(l-methylethyl)-4-piperidiny~benzeneacetamide monohydrochloride; mp. 242 . 9C.

Claims (8)

PROCESS CLAIMS

1. A process for preparing a chemical compound selected from the group consisting of an N-aryl-N-(4-piperidinyl)arylacetamide having the formula:

(I) and the pharmaceutically acceptable acid addition salts thereof, wherein:
L is a member selected from the group consisting of hydrogen, alkyl having from 1 to 10 atoms, cycloalkyl, cycloalkyl-lower alkyl and lower alkenyl;
Ar is a member selected from the group consisting of phenyl, mono- and di-substituted phenyl, pyridinyl and 2-pyrimidinyl, wherein each substituent in said mono- and di-substituted phenyl is independently selected from the group consisting of halo and lower alkyl;
Ar1 is a member selected from the group consisting of phenyl, mono- and di-substituted phenyl, and thienyl, wherein each substituent in said mono-and di-substituted phenyl is independently selected from the group consisting of halo, lower alkyl, hydroxy and lower alkyloxy; and X is a member selected from the group consisting of hydrogen, lower alkyloxycarbonyl and lower alkyloxy-methyl, characterized by a) eliminating the protecting group P by known methods from a compound of the formula (IV) in order to prepare a compound of the formula (I-a) or b) N-alkylating a compound of the formula (I-a) above, by known procedures in order to prepare a compound of the formula (I-b) wherein L1 is the same as L, but other than hydrogen, said N-alkylation preferably being conducted by reacting said compound (I-a) with an appropriate reactive ester of the formula L1-Y, wherein Y is an appropriate reactive ester radical, in an appropriate reaction-inert organic solvent, preferably in the presence of a base, or c) preparing a compound of the formula (I-b) where-in L1 has the meaning of alkyl, cycloalkyl or cyclo-alkyl-lower alkyl only and the carbonatom attached to the piperidine nitrogen has thereon at least one nitrogen atom, by catalytic hydrogenation of a mixture of an appropriate aldehyde or ketone corresponding to the alcohol L1-OH, and a compound of the formula (I-a), in the presence of an appropriate catalyst, or d) by reductive elimination of the phenylmethyl group from a compound of the formula (VI) using catalytic hydrogenation in order to prepare a compound of the formula (I-b) or e) acylating a compound of the formula with an appropriate arylacetyl halide of the formula (III) in a suitable reaction-inert organic solvent preferably in the presence of a base, and, in the instance wherein Ar1 in the final compound (I-b) is mono or di-hydroxyphenyl, alone, or together with other substituents, preferably adding an appropriate protecting group to said hydroxyl or hydroxyls on the starting compound (III), and after the final product is prepared, removing said protecting groups by alkaline hydrolysis, or f) preparing pharmaceutically acceptable acid addition salts of the products of any one of steps a) to e).

2. A process for preparing a chemical compound selected from the group consisting of N-(4-chlorophenyl)-N-[1-(1-methylethyl)-4-piperidinyl]benzeneacetamide and the pharmaceutically acceptable acid addition salts thereof, characterized by reacting N-(4-chlorophenyl)-N(4-piperi-dinyl)benzeneacetamide with 2-bromopropane, and, if desired, preparing a pharmaceutically acceptable acid addition salt of the product thereof.

3. A process for preparing a chemical compound selected from the group consisting of N-(4-chlorophenyl)-N-(1-ethyl-4-piperidinyl)benzeneacetamide and the pharma-ceutically acceptable acid addition salts thereof, characterized by reacting N-(4-chlorophenyl)-N(4-piperi-dinyl)benzeneacetamide with iodoethane, and, if desired, preparing a pharmaceutically acceptable acid addition salt of the product thereof.

4. A process for preparing a chemical compound selected from the group consisting of 3-chloro-N-(1-cyclohexyl-4-piperidinyl)-N-phenylbenzeneacetamide and the pharmaceutically acceptable acid addition salts thereof, characterized by reacting 1-cyclohexyl-N-phenyl-4 piperidineamine with 3-chloro benzene acetyl chloride, and, if desired, preparing a pharmaceutically acceptable acid addition salt of the product thereof.

PRODUCT CLAIMS

5. A chemical compound selected from the group con-sisting of an N-aryl-N-(4-piperidinyl)arylacetamide having the formula:

(I) and the pharmaceutically acceptable acid addition salts thereof, wherein:
L is a member selected from the group consisting of hydrogen, alkyl having from 1 to 10 atoms, cycloalkyl, cycloalkyl-lower alkyl and lower alkenyl;
Ar is a member selected from the group consisting of phenyl, mono- and di-substituted phenyl, pyridinyl and 2-pyrimidinyl, wherein each substituent in said mono- and di-substituted phenyl is independently selected from the group consisting of halo and lower alkyl;
Ar1 is a member selected from the group consisting of phenyl, mono- and di-substituted phenyl, and thienyl, wherein each substituent in said mono- and di-substituted phenyl is independently selected from the group consisting of halo, lower alkyl, hydroxy and lower alkyloxy; and X is a member selected from the group consisting of hydrogen, lower alkyloxycarbonyl and lower alkyloxymethyl whenever prepared or produced by the process of Claim 1 or by their obvious chemical equivalents.

6. A chemical compound selected from the group consisting of N-(4-chlorophenyl)-N-[1-(1-methylethyl)-4-piperidinyl]benzene-acetamide and the pharmaceutically acceptable acid addition salts thereof whenever prepared or produced by the process of Claim 2 or by their obvious chemical equivalents.

7. A chemical compound selected from the group consisting of N-(4-chlorophenyl)-N-(1-ethyl-4-piperidinyl)benzeneacetamide and the pharmaceutically acceptable acid addition salts thereof, whenever prepared or produced by the process of Claim 3 or by their obvious chemical equivalents.

8. A chemical compound selected from the group consisting of 3-chloro-N-(1-cyclohexyl-4-piperidinyl)-N-phenylbenzeneacetamide and the pharmaceutically acceptable acid additon salts thereof, whenever prepared or produced by the process of Claim 4 or by their obvious chemical equivalents.