CA1097646A - Piperazine and piperidine derivatives - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
Novel compounds are disclosed of the formula:

(I) and the pharmaceutically acceptable acid addition salts thereof, wherein:
Ar1 and Ar2 are each independently selected from the group consisting of phenyl, substituted phenyl and pyridinyl, wherein said substituted phenyl is phenyl having from 1 to 2 substituents independently selected from the group consisting of halo, lower alkyl, lower alkyloxy trifluoromethyl and nitro;
m is an integer zero or 1;
A is a member selected from the group consisting of and , provided that when said A is then said m is zero and when said A is then said m is 1;
n is an integer of from 2 to 6 inclusive, provided that when CnH2n represents a branched alkylene chain, then at least 2 carbon atoms are present in the linear portion of the chain linking B with the piperidine or piperazine nitrogen atom; and B is a member selected from the group consisting of:
a) a radical having the formula wherein:
R1 and R2 are each independently selected from the group consisting of hydrogen, halo, lower alkyl and trifluoromethyl; and Y is a member selected from the group consisting of oxygen, sulfur and a substituted nitrogen of the formula , wherein said L is a member selected from the group consisting of hydrogen, lower alkyl, lower alkylcarbonyl, lower alkyloxycarbonyl-lower alkyl, carboxy-lower alkyl, phenyl, phenylmethyl, lower alkylaminocarbonyl, hydroxy-methyl, and lower alkenyl; and b) a radical having the formula wherein:

R1 and R2 are each independently selected from the group consisting of hydrogen, halo, lower alkyl and trifluoromethyl; and M is a member selected from the group consisting of hydrogen, lower alkyl, phenyl, phenylmethyl, mercapto, lower alkylthio, amino, lower alkylcarbonylamino, lower alkyloxycarbonylamino, and cycloalkyl having from 3 to 6 carbon atoms. Theses novel 1-substituted 4-(diarylmethyl)piperazine and 4-(diarylmethoxy) piperidine derivatives having anti-anaphylactic and antihistaminic properties.

Description

BAC~GROUND OF THE INVENTION:

In the prior art there may be ~ound a number of 1- ~ heterocyclyl)alkyl~piperazines and a number of 1-substituted 4-(diarylmethyl)piperazine and 4-(diaryl-methoxy)piperidine derivatives having pharmacological properties, Such compounds are described in the ~ollo-wing re~erences:

U.S~Pat. No. 3,362,g56;
U.S.Pat. No. 3,472,854;
U.S.Pat. No. 3,369,022;
U.S.Pat. No. 2,882,271;
U.S.Pat. No. 3,956,328; and C.A., 64, 3499e (1966).

The compounds of this invention differ from the foregoing essentially by the nature of the B-CnH2n-group, present in the 1-position o~ the piperazine or piperidine groupp and/or by the nature o the diaryl-methyl or diarylmethoxy group present in the 4-position of said piperazine, respectively piperidine group.
:

DESCRIPTION OF THE PREFERRED EMBODIM3NTS:

This invention relates to novel c~emical compounds and more particularly to piperazine and piperidine deri-vatives which may structurally be represented by the formula:
~' B~CnH2n~ ~ ~()m~CH
~(I) ~k and the pharmaceutically acceptable acid addition salts thereof, wherein:

Ar1 and Ar2 are each independently selected from the group consisting of phenyl, substituted phenyl and pyridinyl, wherein said substituted phenyl is phenyl having from 1 to 2 substituents independently selected from the group consisting of halo, lower alkyl, lower alkyloxy, trifluo~omethyl and nitro;
m is the integer zero or 1;

A is a member selected from the group consisting of ~-and ~CE-, provided that when said A is ~ - then said m is zero and when said A is ,CH- then said m is 1;

n is an integer of from 2 to 6 inclusive, provided that when CnH2n represents a branched alkylene chain, then at least 2 carbon atoms are present in the linear portion of the chain linking B with the piperidine or piperazine nitrogen atom; and B is a member selected from the group consisting of:
~ a) a radical having the ~ormula - Y ~ N-., . --3--..

,! :
, ' : : '- ' wherein:
R1 and R2 are each independently selected from the group consisting of hydrogen, halo, lower alkyl and trifluoromethyl; and Y is a member selected from the group consisting of oxygen, sulfur and a substituted nitrogen o~
the formula ~N-L wherein said L is a member selected from the group consis~ing o hydrogen, lower alkyl, lower alkylcarbonyl, lower alkyloxy-carbonyl-lower alkyl, carboxy-lower alkyl, phenyl, phenylmethyl, lower alXylaminocarbonyl, hydroxy-methyl, and lower alkenyl; and b) a radical ha~ing the formula M

N~ N-. . ~

; wherein:

R1 and R2 are each independently selected ~rom : the group consisting of hydrogen, halo, lower alkyl, and trifluoromethyl; and~

: ~ M is a member selected Çrom ~he group consisting ~ of hydrogen, lower alk~yl 9 phenyl, phenylmethyl, ;; 20 mercapto,lower alkylthio, amino, lower alkylcar-~: bo~ylamino, lower alkyloxycarbonylamino, and cycloalkyl having from 3 to 6 carbon a~oms~
:~ :

~7~i46 As used in the ~oregoing and in the following definitions, "lower alkyl" is meant to include straight and branch chained hydrocarbon radicals having from 1 -to 6 carbon atoms such as, for example, methyl, ethyl, 1- methylethyl, 1,1-dimethylethyl, propyl, butyl, pentyl, hexyl and the like; "lower alkenyl" is meant to include straigth and branch chained alkenyl radicals having from

2 to 6 carbon atoms such as, for example, ethenyl, 1-methylethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 1-methyl-2-butenyl, 2-pentenyl, 2 hexenyl and the like;
"cycloalkyl" refers to cyclic hydrocarbon radicals having from 3 to 6 carbon atoms such as, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohe~Jl;
the expression "CnH2n" refers to straight and branch chained alkylene chains having from 2 to 6 carbon atoms and having at least 2 carbon atoms in the linear portion of the chain linking the B-group with the piperidine or piperazine nitrogen~ such as, for example, 1,2-ethanediyl, 1,3 propanediyl, 2~methyl-1,3~propanediyl, 1,~-butanediyl, 2-methyl-1,4-butanediyl, 1,5-pentanediyl, 1,6-hexanediyl and the like; and the term '1halo" is generic to halogens of atomic weight less than 127, i.e., fluoro,chloro, bromo and iodo~ ' The subject compounds of formula (I), except those wherein B stands for a 2~amino-1H-benzimidazol-1-yl radical, may conveniently be prepared by reacting an appropriate reac~ive ester of formula (II~ wherein n is as previously defined, B is as previously defined except a 2-amino~1H-benzimidazol-1-yl radical of the formula . ~,....

~7~
lH2 N ~ _ R R

wherein R1 and R2 are as previously defined, and W is an appropriate reactive ester ~unction derived from the corresponding alcohol such as, for example, halo, methanesulfonyl, 4-metl~ylbenzenesulfonyl and the like, with an appropriate piperidine or piperazine derivative of formula (III) wherein A, m, Arl and ~r2 are as previously defined:
. ~ Ar1 B-CnH2n-~ ~ HN~ -()m-CH ________ ~ (I) (II) (III) The foregoing condensation reaction is preferably carried out in an appropriate reaction-inert organic sol-vent such as, ~or example, a lower alkanol, e.g. methanol, ethanol, propanol,~butanol and the like alkanols; an aYomatic hydrocarbon, e.g~, benzene, methylbenzene, di-methylbenzene and the like; an ethe~, e.g., 1,4-dioxane, 71 '-oxybispropane and the like, a ketone~, e.g9, 4-methyl- -2 pentanone; N,N~dimethylformamide~ nitrobenzene; and the likeO The ad~ition o~ an appropria~e base such as, for example, an al~ali metal or earth alkali metal carbonate or hydrogen carbonate, may be utilized to pick up the acid which is liberated during the course of the reaction.
A small amount o an appropriate metal iodide, e.g., sodium or potassium iodide may be added as a reaction promotor.
-;' , s~

Somewhat elevated temperatures are appropriate to en-hance the rate of the reaction and preferably the reaction is carried out at the reflux temperature or the reaction mixture.

In this and ~ollowing preparations, the reaction products are separated from the reaction mixture and, if necessary, further purified by the application of metho-dologies generally known in the art.

The compounds of Pormula (I) wherein B stands for a 2-amino-1H-benzimidazol-1-yl radical, (I-a), are easily prepared starting from the corresponding compounds (I) wherein B stands for a 2-~ower alkyloxycarbonylamino)-1H-benzimidazol-1-yl radical, (I-b), by decarboxylating the latter under hydrolytic conditions, for example, by acid hydrolysis using an appropriate strong acid, such as hydrochloric, hydrobromic or sulfu~ic acid, or by alkaline hydrolysis using an appropriate strong base such as, for example, sodium or potassium hydroxide.

~H-COO(lower alkyl) Ar1 N ~ ~CnH2n~N 3 -(O)m-CH H or OH

R R
(I-b) NH2 ~ Ar1 N~C~N-CnH2n~N\~ (o)m-c~ 2 G/ ~
R~;=~\R2 (I~a) ~7--, ~7~i~6 It is to be noted that when the B-group in compounds of formula (I) or in intermediates therefor stands for a 2-(lower alkyloxycarbonylamino)-1H-benzimidazol-1-yl or a 2-(lower alkylcarbonylamino)-lH-benzimidazol-1-yl radical, then said radicals may exist in different tautomeric forms as is illustrated hereafter:
NH-COO(lower alkyl) l-COO(lower alkyl) N~C ~ ~ N-~ 2 ` ~ - ` ~

NH-CO-(lower alkyl) N-CQ-(lower alkyl) N~,C`N HN~C~

R~2 R~R2 Such tautomeric forms o~ compounds of formula (I) are natu-rally intended to be within the scope of this invention.

Compounds of formula (I) which may be represented by the formula (I-c):

, n~2n ~ -(O)~-C

(I-c) ~ ' X

.

~7~

wh~rein R1, R2, n, A, Ar1 and Ar2 are as previously defined may alternatively be prepared by ring closure of an appropriate intermediate of formula (IV) with an appropriate cyclizing agent as known in the art for the preparation of 1,3-dihydro-2H-benzimidazol-2-ones starting from 1,2-benzenediamines.
Suitable cyclizing agents which may advantageously be employed include, for example, urea, carbonyl dichloride and alkali metal isocyanates, and the cyclization reaction 10 may be performed ollowing methodologies generally kno~n in the art~ For example, when urea is used as the cyclizing agent the compounds (I-c) are easily obtained by stirring and heating the reactants together in the absence of any solvent.
The foregoing preparations may be illustrated as follows.

H2~ CnH2n-N/ \A-(O)m~C~

, (IV) cyclizing (I-c) .
agent The compounds of formula (I-c~ may still be pre-pared starting from the corresponding compounds of : formu1a (V). R Ar1 P-~ ~ ~CnH2n~ ~ A ( )m ~ A~2 R1 ~2-(V) _g_ .. . . . ... . . . . . . .
. . - . . - . .
.. : . . - ~ . , , ~ -:: , . . .. . ..

~ ~ 7 ~ ~

wherein R1, R2, n, A, m, Ar1 and Ar are as previously defined and P is an appropriate protecting group, by the removal of said protecting group according to conventional procedures. As examples of such protecting groups there may be mentioned lower alkyloxycarbonyl and, a substituted ethenyl group of the formula R -CH=C-l3 wherein R3 and R4 may represent different groups but wherein R3 is preferably lower alkyl and R4 is preferably hydrogen, lower alXyl or phenyl.

When the protecting group is lower alkyloxycarbonyl, it may easily be removed by alkaline hydrolysis, and when the protecting group is a substituted ethenyl group it is conveniently eliminated by subjecting the appropriate intermediate (V) to acid hydrolysis. In carrying out the acid hydrolysis to remove the substituted ethenyl group from (V) a wide variety of protonic acids may be employed, including mineral acids such as, for example, hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acid, and organic acids such as, for example~ acetic, propanoic, ethanedioic and the like acids. Further the reaction may be carried out in reaction inert organic solvents as commonly employed in such a type of hydrolytic reactions, e.g~ 9 lower alkanols such as, for example, methanol, ethanol, 2-propanol ~nd the like.

In a procedure similar to that described for the preparation of the compounds (I-c) starting from (IV) the~e may also be prepared compounds of the formula (I-d) .

~7~

N~--~N-cnH2r-N~-(o)m R1 ~2 (I-d) wherein R1, R2, n, A, m, Ar1 and Ar2 are as previously defined, and M1 is selected from the group consisting of hydrogen, lower alkyl, phenyl, phenylmethyl, mercapto, amino, lower alkyloxycarbonylamino and cycloalkyl, by the reaction of (IV) with an appropriate cyclizing agent, Pollowing art-known methodologies of preparing 1H-benz-imidazoles starting from 1,2-benzenediamines. Depending on the nature of M1 in the compounds (I-d) the following cyclizing agents may, for example, be employed.
.
When M`1 stands for hydrogen there may be used formic acid or an appropriate tri(alkyloxy)methane as a cyclizing agent.
When M1 stands for lower alkyl, phenyl, phenylmethyl or cycloalXyl, one may use a carboxylic acid of the formula ~ ~ R5-CooH
:;
~ VI) , , ~
wherein RS is lower alkyl, phenyl, phenylmethyl, or cyclo alkyl, or a functional derivative thereof such as, for example, an acyl~halide~ an ester, an amide or a nitrile derived from such acid or an~imlnoester of the formule /0-(lower alkyl) HN=C
\R5~
(VII) ~ ~ :

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

7~

wherein R5 is as defined hereabove; or an aldehyde of the formula R5-C~
~H
(VIII) or an addition product thereof with an alkali metal hydrogen sulfiteO When the cyclizing agent is an aldehyde there may be added to the reaction mixture an appropriate oxidizing agent such as, for example, nitrobenzene, mer-curic oxide, Cu(II) and Pb (II) salts or other suitable oxidants as known in the art, or the aldehyde itself, when added in excess, may serve as an oxidant.

When ~1 stands for mercapto t~ere may be used cyclizing agents such as, for example, carbon disulfide, thiourea, carbonothioic dichloride, ammonium thiocyanate and the like.
.~
~hen M1 is an amino group, ring closure may be performed with cyanamide, or a metal salt thereof, preferably an alkali or earth alkali me~al salt 7 or with BrCN.

When M1 stands for lower alkyloxycarbonylamino, one may use as a cyclizing agent,for example,an appropriate lower alkyl (iminometho~ymethyl)carbamate of the formula (IX) N~ O
H3C-0-~-NH ~-O(lower alkyl); or (IX) ' .

, _ :

~ ~ 7f~

a lower alkyl ~ lower alkoxycarbonylamino)(P~6-thio)-methylene~carbama~e of the formula (X) ~6 o S O
(lower alkyl)-0-~-N-C=N-~-0-~lower alkyl) (X) wherein R6 is hydrogen or methyl; or a lower alkyl carbonoi50thiocyanatidate of the formula (XI) (lower alkyl)-0-C-NCS; or (XI) : 5 a lower alkyl lower alkylcarbamothioate of the formula ~ (XII) ~ S
(lower alkyl)~NH-~-0-(lower alkyl); or (XII) a dilower alkyl cyanimidodicarbonate of the formula (XIII) .

lower alkyl)-0- ~2N-CN

(XIII) The foregoing cyclization reactions ma~ all be : perf:ormed followlng well-known methodologies as described in the literature.~

"' Compounds of the formula (I-e) NH-CO~(lower alkyl) Arl N, ~--CnH2n--N\__~A ( )m \ Ar2 R1 ~2 (I-e) may alternatively be prepared by the acylation o~ an appropriate 2-amino-1H-benzimidazol-1-yl derivative of formula (I-a) ~ollowing standard N-acylati~g procedures, e.g., by the reaction of (I-a) with an appropriate lower alkylcarbonyl halide or with an anhydride derived ~rom a lower alkylcarboxylic acid.

Compounds of the formula (I-f) L1-N'~ -Cn~2n~ ~ ~~()m \ A 2 ., R1 R2 (I-f) where m R1, R2, n, A, m, Ar1 and Ar2 are as previously defined and L1 is selec~ed from the group consisting of lower alkyl, lower alkylcarbonyl, lo~er alkyloxycarbor.yl-lower alkyl, carboxy-lowex alkyl, phenylmethyl, lower alkylaminocarbonyl~ hydroxymethyl and lower alkenyl, provided that the unsaturation in said lower alkenyl is located in a position other than ~ , may still be pre-pared by the introduction of said L1 into a compound o~
~ormula (I-c) .

-~4-'~

I I /Ar1 HN ~ -CnH2n-N A-(O)m-CH

Depending on the nature o~ the L1 group to be intro-duced the following methods may be utilized therefor.

When L1 stands for lower alkyl, lower alkyloxycar-bonyl-lower alkyl, phenylmethyl or lower alkenyl, in which case the symbol L1a is used thereor, the intro-duction of said L1a into (I-c) may be performed by the reaction of (I-c) with an appropriate reactive ester of the ormula L1a-W9 (XIV), wherein L1.a is as defined hereabove and W has the same meaning as assign~d to it in the definition of the starting materials of formula (II).

The condensation of (XIV) with (I-c) may be car~ied out under similar conditions as described hereinbefore for the condensation of the reactive esters ~II) with the interm~diates of formula (III), In order to enhance the reaction rate i~ may be appropriate in some ins~ances to add to the reaction mixture a small amount of an appropriate macrocyclic polyether such as, or example 2,3911,12-dibenzo 1,4~7,10,13,16 hexaoxacyclo-octadeca-2,11-diene as a reac~ion promotor~

When the L1 group to be introduced 7 s lower alkyloxy-carbonylethyl, the introduction of said group may alter--7~L6 natively be performed by reacting (I-c) with a (lower alkyl) 2-propenoate of formula (XV) (lower alkyl)OOC-CH=CH2 (XV) Said reac-tion may conveniently be carried out in a reaction-inert organic solvent such as, for example, an aromatic hydrocarbon, e.g., benzene, methylbenzene, dimethylbenzene and the like; an ether, e.g., 1,1'-oxybisethane, 2,2'-oxybispropane, tetrahydrofuran, 1,4-dioxane and the like, pre~erably in the presence of an appropriate aminium hydroxide such as, for example, N,~,N-triethylbenzenemethanaminium hydroxide.

Compounds of formula (I-f) wherein L1 stands for carboxy-lower alkyl can easily be derived from the corresponding lower alkyloxycarbonyl-lower alkyl sub-stituted compounds by hydrolyzing the latter in the ; 15 usual manner, eOg~, with aqueous alkali, ~o liberate the acid from the ester.

When the L1 group is lower alkylcarbonyl said group may onveniently be introduced by the reaction of (I-c) with an appropriate acylating agent derived from the ~o correspo~ding lower alkylcarboxylic acld such as~
Por example, a halide, preferably the chloride, or an anhydride, following standard N-acyIating procedures.

When L1 stands for lower alkylaminocarbonyl it may be introduced by the reaction of (I-c) with an appropriate isocyanatoalkane in an appropriate reaction-inert organic solvent such as, for example, an ether, e.g., 1,1'-oxy-bisethane, 2,2'-oxybispropane, 1,4 dioxane and the like.

-16~

~ ~ ~ 7 ~ ~

When L1 is a hydroxymethyl group its introduction is conveniently performed by the reaction of (I-c) with formaldehyde in an appropriate organic solvent such as, for example, N,N-dimethylformamide.

Compounds of the formula (I-g) ~ ~ ~Ar1 B CnH2n ~ ~ \ Ar2 (I-g) wherein B, n, Ar1 and Ar2 are as previously defined may : alternatively be prepared by the condensation of a piper- -azine derivative of formula (XVI) with an appropriate rea-ctive ester of formula (XVII) wherein Ar1, Ar2 and W are as previously defined, under similar conditions as des-: 15 cribed hereinbefore for the preparation of the compounds (1) starting from (II) and (III).

~ /Arl B-CnH2n-N~ NH ~ ~ Ar2 ~~~~~~~~~ g) (XVI~ (XVII) :

~17-, X

Compounds of the formula (I-h) -(lower alkyl) ~,C~ ~----\ ~ A~
N ~ ~C H2 -N A-(O) -CH

(I-h) are also conveniently prepared starting Prom the corres-ponding -SH substituted analogs by standard S-alkylating procedures, e.y., by the reaction of the mercapto com-psund with an appropriate halo-lower alkane in an approp-riate orga~ic solvent such as, for example, a lower alkanol, e,g., ethanol, propanol, 2-propanol, butanol and the like.

A number of the intermediates of formula (II) are known compounds and some of them are descri~ed in U.S.
Pat. Appln. Ser. No. 597~793, filed July 21, 1975 and in ~.SOPat. Appln. Ser. No. 620,727, filed October 8, 1975, and they may all be prepared follo~Jing methodologies which are known per se. Dep nding on the nature oP B in said intermediates (II) the following procedures m~y be utilized for preparing them. ~ ~
Intermedlates of the formula (II-a) HN' I C H W

a)~

. .

~r~

,~

7~6 may be prepared as follows:

An appropriately substituted 2-chloronitrobenzene of formula (XVIII) is reacted with an appropriate amino-alkanol (XIX) by refluxing the reactants together in an appropriate reaction-inert organic solvent such as, for example, a lower alkanol, e.g., ethanol, propanol, 2-propanol, butanol and the like, whereupon a ~ 2-nitro-phenyl)amino~alkanol o formula (XX) is obtained, which in turn is subjected to a nitro-to-amine reduction, e~g., by catalytic hydrogenation using Raney-nickel catalyst.
The thus obtained intermediate (XXI) is then reacted with an appropriate cyclizing agent as described hereinbefore for the preparation of the compounds (I-c) starting from (IV), and the thus obtained alcohol of formuIa (XXII) is subsequently converted into the desired reactive ester (II-a) by the application of methodologies known in the art.
Halides are conveniently prepared by the reaction of (XXII) with an appropriate halogenating agent such as, for example, sulfinyl chloride, sulfuryl chloride, phosphor pentachloridS
phosphor pentabromide, phosphoryl chloride and the like.
When the reactive ester is an iodide, it is preferably derived from the corresponding chloride or bromide by the replacement of that halogen with iodine. Other reactive esters such as methanesulfonates and 4-methylbenzenesul-~onates are obtained by the reaction of the alcohol with an appropriate sulonyl halide such as, for example, methane sulfonyl chloride and ~ methylbenzenesulfonyl chloride respectively.

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

~T

~7~

02N Cl H2N-CnH2n-OH

R1 R2 (XI~) (XVIII) 02N NH CnH2n OH
~ H2 / RaNi (XX) H2N NH-CnH2n-OH
ring closure (XXI) O
N-CnH2n~0H
reactive ester a) formation (XXII) ~-~, , ~ ~ 7~ ~

Alternatively the intermediates o~ ~ormula (I~-a) : may also be prepared by:

i) reacting a compound of formula (XXIII) wherein R3 and R4 are as previously de~ined with a haloalkanol o~ formula (XXIV) by conventional N-alkylating pro-cedures to obtain an alcohol of formula (XXV);

ii) converting the hydroxyl function o (XXV) into a reactive ester group in the usual manner as pre-viously described; and iii) eliminating the su`bstituted ethenyl group of the thus obtained (XXVI) by acid hydrolysis as described hereinbe~ore for the prepara~ion of (I-c) starting ` ~rom (V).

The introduction o~ the hydroxyalkyl chain in (XXIII) to obtain (XXIV) may also be performed by the reaction of (XXIII) with an appropriate 2-(haloalkyloxy)tetrahydro-: 2H-pyran of formula (XXVII), yielding an intermediate o~
formula (XXVIII), the ether function o~ which is hydro-lytically split open, e.g., by the treatment with an aqueous hydrochloric acid solution.

When the reactive ester (II-a) is a halide, (II-a-1), it may alternatively b prepared by the reaction o~
(XXIII) with an equivalent amount o~ an appropriate di-haloaIkane, (XXIX) in the presence of an appropriate strong base such as, for example, sodium methoxide, or following a Mackosza procedure using aqueous alkali and a quaternary ammonium catalyst, e.g., N9N,N-triethylbenzenemethan~ninium chloride, yielding an intermediate of formula (XXVI a), the substituted ethenyl~group of which is subsequently removed 0 by acid hydrolysis, to yield the desired halide (II-a-1).
' , ~

:`

~q~

It is to be noted that the same procedures are also applicable ~vhen the substituted ethenyl group is replaced by another appropriate protecting group, except that removal thereof has to be performed following appropriate methods for the elimination of the par-ticular group involved.

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

,~;
- : :

,, ~
:

I `

. ~ -22-, ~ , ,~.
i, . , - ' , ~

7~

o ~1: H ,S~
S X I (~
V X
O
V ~ X
C H

~ ~ X
/ ~
/
~ 0 O ~
O _~
~U ~ I ~
p:~ H S: H
V ~ ~ ~
O ~ V X

='b~
I C'~ I
~VI~y C)--K H

~: \ ~0 \~+~1 d~
O

V ~ V c,

3~ ~ 3~
V~ ~

.

. .
.
.

7~

Intermediates of the formula (II-b) o n 2n R~R2 (II-b) wherein R1, R2, n and W are as previously defined and ~2 is selected from the group consisting of lower alkyl, lower alkenyl, lower alkyloxycarbonyl-lower alkyl, phenyl, phenylmethyl and lower alkylaminocarbonyl, may conveniently be prepared by the introduc~ion of the reac-tive ester side chain into a starting material of the formula (XXX).

~1 , . L2~N'C ~ H

; ~ 2 R R

(X~) ~

ollowing similar procedures to those described ~erein-~;: 10be~ore for the preparation of the intermediates (XXVI) :~: starting from (XXIII).

Intermediates of the formula (II c) HocH2~ cnH2n ; R ~ R2 (II-c) ~ -24~
,, . , -~7~

may be prepared starting from the corresponding (II-a) by hydroxymethylation of the latter in the usual manner with formaldehyde.
Intermediates o~ the formula (II-d) -CnH2n-W
N ~ I

(II-d) except those wherein M stands for a mercapto or lower alkylthio group, are conveniently o~tained by the intro-duction of the reactive ester side chain into a starti-ng material of the formula (XXXI) M
N~C~H

. 1 R R
(XXXI) The introduction of the CnH2n-W grGUp may be performed following similar procedures ~o those described herein-before for the introduction of said group into starting ;: materials of formula (XXIII).
; ; ' . .

:

3~Q~

I-ntermediates of formula (II e) ~C ~N-C H2 -W

~1 R2 (II-e) wherein R1, R2, Ml, n and W are as previously defined, may be prepared by subjecting an appropriate alcohol of formula (XXI) to ring closure with an appropriate cyc-lizing agent as described hereinbefore, followed by the conversion of the hydroxyl group of the thus obtained intermediate of ~ormula (XXXII) into a reactive ester group .
~[1 (XXI) cyclization> N~ ~ -C H2 -OH reactlve ester (II-e ~ formation ~,' (XXXII) The intermediates of the ~ormula (II-~3 ;~ ~ S-(lower alkyl) -N~'b`N C H W

. :
f) ::

,~

~ ~ ~ 7 6 ~

are conveniently obtained by S-alkylation of an appropriate intermediate of formula (XXXII), wherein Ml stands for mercapto (XXXII-a), following standard S-alkylating pro-cedures, e.g. with an appropriate halolower alkane and subsequent conversion o~ the hydroxyl ~unction of the thus obtained (XXXIII) into a reactive ester group.
SH S-(lower alkyl) N~~CnH2n~H S-alkylation N `~~CnH2nH
>~

(XXXII-a) (XXXIII) reactive ester (II-f) . : ~
formation Intermediates of the ~ormula (II-g) NH-CO-(lower alkyl) N'~ ~CnH2n~W

R R

g) are conveniently prepared by N-acylation of the cor-responding amino substituted analog, (II-h), N\~ cnH2n-w R = 2 h) : -27-.
,', ' ~7~

following procedures known to those skilled in the art, e.g., by the reaction of (II-h) with an appropriate lower alkylcarbonyl halide or with an anhydride derived from an appropriate lower alkylcarboxylic acid.

The intermediates o~ ~ormula (IV) are obtained by the condensation of an appropriate reactive ester of formula (XXXIV) with a piperazine or piperidine deri~ative of formula (III) followed by the reduction of the nitro group of the thus obtained intermediate (XXXV) to an amino group according to standard nitro-to-amine reduction pro-cedures, e.g., by the reaction of the nitro compound with nascent hydrogen or by catalytic hydrogenation in the pre-sence of an appropriate catalyst such as, for example, Raney nickel.

- 2~ ~ NH-CnH2n-W
~ ~ (III) >
R1 ~2 (XXXIV) Ar 2N ~ NH-C H2 - ~ A-(0) ~CH
r nitro-to-amine reduction ~X~V) '~

.

' , , , ~7~

The reactive esters of formula (XXXIV), used as starting materials herein are easily prepared from an alcohol of ~ormula (XX) by the conversion of the hydroxyl ~unction thereo~ into a reactive ester group following standard procedures as previously described herein.

The intermediates of formula (V) may be obtained by the condensation of a reactive ester of formula (XXXVI) with a piperazine or piperidine derivative of formula (III) Il P_N~C~T_CnH2n_W
+ (III) ~ > (V) ~,1 R2 (XXXVI) The reactive ester (XXXVI) used as a starting material herein is in turn prepared by introducing the CnH2nW
group into a starting material o~ formula (XXXVII) p_ ~ H
~ .
R~ 2 (XXXVII) :; :
following the procedures described hereinbefore.

.

~7~

The intermediates of ormula (XVI) may be prepared by the reaction of a reactive ester of formula (II) with a piperazine derivative of formula (XXXVIII) wherein Q i, an appropriate protecting group such as, for example, phenylmethyl or lower alkyloxycarbonyl, and subsequently eliminating said protectiny group Q from the thus obtained intermediate (XXXIX) following standard procedures as known in the art, for example, by catalytic hydrogenation using palladium-on-charcoal catalyst when Q stands for phenylmethyl, or by alkaline hydrolysis when Q stands ~or lower alkyloxycarbonyl.

A ~
(II) ~ HN N-Q _ ~ B-CnH2n~N~ N-Q

(XxxyIII) (XxxIx) elimination o~ Q (XVI) Intermediates of formula (XVI-a) ., .

. ~ `N CnH2n~-N ~ ~
'''' ~2' . ~ .

(XVI-a) "
' 'X

.

37~

may alternatively be prepared by the reaction of (XXXVI) with (XXXVIII) to obtain an intermediate o~
formula (X~) and su~sequently eliminating the protecting groups P and Q by appropriate procedures as generally kno~vn in the art.
O

(XXXVI) -~ (XXXVIII) ~ P ~ CnH2n ~ N-Q
~/ ~
Rl R2 (~) eIimination of ~ -C H2 ~ ~ ~Q
P
; ~ 2 (XXXIX-a) elimination of (XVI-a) ~: ~ ~ >

Intermediates of formula (III) wherein A is N-and m is 0, (III-~), are generally known and they may all be prepared by the application of methodologies know~ in the art. Such intermediates (III-a3 may for example, be prepared by first subjecti~g an appropriate aroyl halide to a Friedel-Crafts reaction with an appropriate arene to ob-tain an Ar1, Ar2-methanone ~rhich in turn is reduced in the usual manner, e.g., with sodium borohydride to the corres-ponding methanol. The latter is then converted into a reacti~e ester (XVII) following standard procedures of preparing reactive esters starting Prom alcohols and the desired intermediates (III-a) are subsequently obtained by the reaction of (XVII) with piperazin~.

. " ' . :

~ 7 ~ ~

The inte-rmediates of formula (III) wherein A is ,CH-and m is 1,(III-b), may conveniently be prepared by O-alkylation of a 4-piperidinol of formula (XII) wherein Q
is an appropriate protecting group as previously defi-ned with an appropriate reactive ester o~ ~ormula (XVII), followed by the removal o~ the protecting group o~ the thus obtained (XLII) in the usual manner.

H / ~ Q-N ~
OH \ Ar2 ~ Ar2 (XLI) (XVII) (XLII) Ar1 removal o~ Q` ~ O-CH
Ar2 (III b) The primary starting materials used in all of the foregoing preparations are generally known and they may all be prepared following methodologies known to those skilled in the artO

The compounds o~ formula (I) may be converted to the therapeutically active non-toxi~ acid addition salt form by treatment with an appropriate acid, such as, for examp-le, an inorganic acid, such as hydrohalic acid, e.g., hydrochloric, hydrobromic, and the like, and sul~uric acid, `~

~f~

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

7~

nitric acid, phosphoric acid and the like; or an organic acid, such as, for example, acetic, propanoic, hydro~y-acetic, 2-hydroxypropanoic, 2-oxopropanoic, propanedioic, butanedioic, (Z)-2~butenedioic, (E)-2-butenedioic, 2-hydroxybutanedioic, 2,3-dihydroxybutanedioic, 2-hydroxy-1,2,3-propanetricarboxylic, benzoic, 3-phenyl-2-propenoic, -hydroxybenzeneacetic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesul-famic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids. Conversely, the salt form can be con-~erted by treatment with alkali into the free base form.

The subject compounds of formula (I) and the pharma-ceutically acceptable acid addition salts thereof possess strong anti-anaphylactic and antihistaminic properties and as such they are useful agents in human and animal therapy. The useful anti~anaphylactic and antihistaminic properties of the compounds o this invention are clearly demonstrated by the results obtained in the test pro cedures described hereafter.

It is emphasized that the compounds listed in the accompanying tables are not given for the purpose of limiting the invention thereto, but only to exemplify the useul anti-anaphylactic and antihistaminic properties oÇ all the compounds vithin ~he scope oÇ Çormula (I).

, ,. .~, , - ~ ', ' ' '' ' ' a7~

Ao Materials and methods.

a) Anti-anaphylactic and antihistaminic effects in "vivo~'.

The anti-anaphylactic and antihistaminic efects of the subject compo~ds (I) and salts thereof are studied "in vivo" in guinea pigs.
Guinea pigs, weighing between 400 and 500 g, are sensitized to ovalbumin by subplantar (s.p.) injection of 0 05 ml of antiserum in the left hind paw. The animals are then star-ved and orally ~reated, 24 hours after the sensitization, with saline (= con-trol animals) or a particular dose of the compound under investigation.
The his~amine injection (at a dose of 50 ~g) was given s.p.
in the right hind paw 2 hours after the oral pretreatment with the compoundO The diameters of both hind paws a~e first measured before the histamine injection is given and again 10 minutes thereafter. The animals are challenged intra-venously with 0.6 mg of ovalbumin 30 minutes after the histamine injection. All control animals develop typical primary anaphylactic shock symptoms (coughing, difficult breathing, convulsions) and 85% of these control animals die whithin 15 minutes after the ovalbumin injection.
Protection against death is used as the criterion for possible drug ef~ects and the estimated ED50-value, iOe.
the oral dose whereby the protection is observed in 50%
of the guinea pigs, is list~d in the tables below.
- The median histamine paw cedema in 200 control animals 10 minutes after the histamine lnjection is 15 units (1 unit = O.1 mm). Reactions below 10 units, occuring in less than - 5% of the control animals are defined as ef~ective in-hibition of histamine oe dema in the compound-treated animals and the oral dose-levels whereby this effective inhi~ition is seen, is also listed in the following tables.

:, :. , . , ~

~7~

b) Anti-histamine activity in "vitro".

Guinea-pig ileum strips are suspended in a 100 ml Tyrode bath at 37.5C with a preload of 0.75 g and gassed with 95% 2 and 5% C02.
The histamine - (0.5 mg/liter) induced spasms are recor-ded K~mographically with an isotonic lever giving a 5-fold magnification. The interaction of the compound to be tested (5 minutes incubation time) with the agonist is studied and the tables below give the efective con-centration (in mg/l) o~ the di~ferent compounds whereby a significant inhibition (50%) of the histamine-induced contraction is measured.

As a result of the foregoing tests t the subject compounds (I) and pharmaceutically acceptable salts thereof are generally found active as anti-allergic agents in doses ranging from about 0.25 to about 20 mg/kg body weight upon systemic administration to warm-blooded animals.

In view of their useful antihistaminic and anti-anaphylactic activity, the subject compounds may be formulated into various pharmaceutical forms for admini-stration purposes. To prepare the pharmaceutical composi-tions of this invention, an efective antihistaminic or anti-anaphylactic amount of the particular compound, in base or acid-addition salt orm, as the acti~e ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on -the form of preparation desired or administration.

,, .

~7~

These pharmaceutical compositions are desirable in unitary dosage form suitable, preferably, for administra-tion orally, rectally or by parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in -the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid car-riers such as starches, sugars, kaolin, lubricants, binders, disintegra-ting agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed~ For parPnteral composit~ns, the carrier will usually comprise sterile water, at least in large part, though other in-gredients, ~or example, ~o aid solubility, may be included.
Injectable solutions, for example may be prepared in which the carrier comprises saline solution, glucose solution or à mixture of saline and glucose solution. Injectable sus-pensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. Acid addition salts of (I), due to their in-creased water solubility over ~he corresponding base form, are obviously more suitable in the preparation of aqheous compositions.

~7~

It is especially advantageous to formulate the aorementioned pharmaceutical compositions in dosage unit ~orm ~or ease of administration and uniformity o~ dosage.
Dosage unit ~orm as used in the specification and claims herein re~ers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired ~herapeutic e~ect in association with the re-quired pharmaceutical carrier. Examples of such dosage unit ~orms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solut-ions or suspensions, teaspoonfuls, tablespoonfuls and the like; and segregated multiples thereo~.

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7~a~6 The following examples are intended to illustrate but not to limit the scope o~ the present invention.
Unless otherwise stated all parts therein are by weight.

~, .: .
:

:

.~ :

.

~ 7 Ex~lple To a stirred and hot mixture of 54 parts o~ 1,3-dihydro 1-(phenylmethyl)-2H-benzimidazol-2-one, 47.25 parts of 1-bromo-3-chloropropane and 6 parts o N,N,N-triethylbenzenemethanaminium chloride are added drop-wise 450 par~s of sodium hydroxide solution 60% at 60C. Upon completion, stirring is continued for 6.
hours at 60C. The reaction mixture is cooled and poured on~o water. The oily product is extracted wi~h trichloro-methane. The extract is dried, filtered and evaporated.
The residue is crystallized from 2,2'-oxybispropane, yielding, after drying, 42 parts (58%) o~ 1-(3-chloro-propyl3-1,3-dihydro-3-(phenylmethyl)-2H-benzimidazol-2-one.

Similarly ~ere prepared:
,~ .
L N `N-(CH2)n-Cl 4 ~ 7 : 5 ~ 6 . -.
. . .. . ~ . ., . ...... .
L ~1 n boiling point ~ . . .. ~ ....
=C(CH3) 5-CH3 3 140C at 0.015 mm. pressure.
C~2=C(CH3) 6-CH3 3 140C at 0,02 mm. pressure C6H5 5~Cl 3 _ C~2=C(CH3) H ~ . ~ .
CH2=C(CH3) H 5 . _ .
CH2_C(CH3) H 6 ~ , = ..

~ .
., .

1`, :

~7~

Example II

Following the procedure of Example I and using an equivalent amount of an appropriate 1H-benzimidazole as a starting material there were obtained as a residue:
M

N~~CnH2n~

_ _ ~ M CnH2n .

CH3(CH2)3 :, .,. ~>(CH2)3 : C2H5(CH2)3 ': , C6~5(CH2)3 : CH3(CH2)4 , ~ ~-: .

~ -48 :

.

~ ' , .
~ , : ~ .

7~
Example III
.
A mixture of 20 parts of 3- ~ 2-amino-4-chloro-phenyl)amin~7-1-propanol, 50 parts o~ acetic acid and 150 parts of hydrochloric acid solution 4N is stirred c~nd refluxed overnight. The reaction mixture is cooled and evaporated. The residue is dissolved in water and the solution is alkalized with ammonium hydroxide. The product is extracted ~ith trichloromethane. The extract is dried, ~iltered and evaporated. The residue is crys-tallized ~rom a mixture o~ 4-methyl-2-pentanone and 2,2'-oxybispropane, yielding 6.5 parts (28%) of 5-chloro-2-methyl-1H-benzimidazole-1~propanol.

Similarly there ~as prepared 5-chloro-2-ethyl-1H-benzImidazole-1-propanol by the reaction of 3-2-amino~4-chlorophenyl)amin ~ -1-propanol ~ith pro-pangic acid.
.

Example IV

To a stirred and refluxing (water-separator) mixture of 30 parts o~ 3-~ 2-amino-4-chlorophenyl)amino~-1~propanol and 0.1 parts of 4-methylbenzenesul~onic acid in 405 parts o methylbenzene is added dropwise a sol-ution o~ 34 parts of ~yclohexanecarboxaldehyde in 45 parts of methylbenzene. Upon completion, stirring is continued ~or 1 hour at re~lux ~mperature and ~ith water-separator. The methylDenzene is removed by eva-poration in vacuo and the residue is triturated in 2,2'-oxybispropane. The product is filtered of~ and dried, yielding 16.5 parts (38%) of 5-chloro-2-cyclohexyl-lH-benzimidazole-1-propanol, mp~ 95C.

.

~, -~

.
. .

76~

Example V

A mixture o~ 30 parts of 3-~ 2-amino-4-chloro-phen~l)amino~-1-propanol, 44.8 parts of sodium ~ -hydroxybenzeneethanesulfonate and 120 parts of ethanol is stirred and refluxed for 30 minutes. The reaction mixture is evaporated and the residue is ta-ken up in water. The oily product is extracted with trichloromethane. The extract is dried, ~iltered and eva-porated, yielding 45 parts (100~) of 5-chloro-2-(phenyl-methyl)-1H-benzimidazole-1-propanol as a residue.

Similarly there was prepared 6-chloro-2-cyclo-hexyl-1H~benzimidazole-1-propanol; mp. 120.1C by the reaction of 3~ ~2-amino-5-chloropheny~)amino~ pro-panol ~ith sodium ~-hydroxycyclohexar.emethanesul~onate.

Example VI
.
To a stirred mixture of 93 parts of 3-(2-amino-phenyl)a~ino-1-propanol, 45.5 parts o~ potassium hydro-xide and 600 parts of ethanol 85% in ~ater are added dropwise 60.8 parts of car~on disulfide. Upon com-pletion~ stirring is continued for 6 hours at re~lux temperature. The reaction mixture is evaporated and the ~esidue is taken up in 1500 parts of water. The whole is filtered over hyflo an~ the filt~ate is aci-dified ~ith acetic acid. The oily product solidifies on scratching. I~ is filtered o~, washed with water and dried, yielding 92 parts (78.9%) of 2 mercapto-1H-benzimidazole-1~propanol; mp. 110C.

" -r .i.~ _ ~ ~ 7 ~

A mixture of 20.8 parts of 2-mercapto-1H-benzimida-zole-1-propanol, 15.62 parts of iodomethane and 120 parts of methanol is stirred overnight at room temperature. The reaction mixture is evaporated and the residue is disso1ved in 500 parts o~ water. The solution is filtered over hyflo and the filtrate is alkalized with solid potass-ium hydro-xide. The oily product is extracted with trichloromethane.
The extract is dried, filtered and evaporated, yielding 19 parts (85.5%) o~ 2-(methyl~hio)-1H-benzimidazo~1-propan as a residue.

To a stirred mixture of 19 parts of 2-(methylthio)-1H-benzimidazole-1-propanol, 15.2 parts o~ N,N-diethyl-ethanamine and 195 parts o~ dichloromethane are added dropwise 11~5 parts of methanesulfonyl chloride. Upon completion, stirring is continued ~or 1 hour at reflux.
After cooling, water is added and the layers are sepa-rated. The organic phase is dried, filtered and evaporated, yielding 19 parts of 3-~ -(methylthio)-~H-benzimidazol-1-y ~propyl methanesulPonate as an oily residue.

E~ple VII
.
A ~ixture o~ 30 parts of 1H-benzimidazole, 49 parts i of 2-(4-chlorobuto~y) tetrahydro-2H-pyran, 21 parts of potassium hydroxide and 200 parts of ethanol is stirred and ref1uxed overnight. The reaction mixture is cooled to room temperature, ~iltered and the filtrate is eva-porated~ The residue is s~irred in water and acidiCied with a diluted hydrochloric acid solution. The whole is stirred and heated ~or 30 minutes in a water-bath. After cooling to room temperature, the product is extr~cted with me~hyl-benzene. The aqueous phase is separated and alXali~ed with ammonium hydroxide5 The product is extracted with dichloro-methane. The ext~act is dried, ~ ere~ and evaporated, - yielding 50 parts o~ 1H-benzimidazole-1-butanol as an oily residue.

, , :
.

Example VIII

To a stirred mixture o~ 5 parts o~ 4-chloro-1,3-dihydro-3-(3-hydroxypropyl)-2H-benzimidazol-2-one and 75 parts of trichloromethane are added dropwise 8 parts oP sul~inyl chloride. Upon completion, stirring i5 con-tinued for 3 hours at re~lux temperature. The reaction mixture is cooled and evaporated. The residue is stirred in a small amount o~ 4-methyl-2-pentanone. The product is ~iltered of~ and dried, yielding 3.5 parts of 4-chloro-3-(3-chloropropyl)-1j3-dihydro-2H-benzimidazol-2-one.

In a similar manner the ~ollowing 1-(chloro-alkyl) 1H-benzimidazoles were prepared:

7-(CH2)n-Cl 4 ~ ~ 7

5 ~ 6 R

n R1 - Base or Salt Mcl~
_ ._ ~, ,

6 5 2 3 5 Cl base _ CH3 3 5-Cl ~ base C2H5 3 5-Cl base _ 3 5-Cl HCl 211~7C

C6H5-CH2L 3 . H base 112C
~_________ ____ _____~. _ _____ _____ _____________ ;

.. . . .

. .

, ~$~

________ _____ ______. ________ _______________ n ~ R1 Base or ~elting point _ _. ~
3 6-Cl HCl 227.5C

C2~5 2 H base ~ 4 H base _ Example IX

A mixture of 113.2 parts o~ 1t2,4-trichloro-5-nitrobenzene, 75 parts of 3-amino-1-propanol, 0.2 parts of potassium io~ide and 200 parts o~ butanol is stirred and refluxed overnight. The butanol is removed by e~a-poration in vacuo and water is added to the residue. The product is extracted with 4-methyl 2-pentanone. The extract is washed a few ~imes ~ith water, dried, filtered and evaporated. The oily residue is puriied by column-chromatography over silica gel using a mixture of tri-chloromethane and 5% of methanol as elu~nt~ The pure fractions are collected and the eluen~ i5 evaporated.
The residue is triturated in 2,2'-oxybispropane. The product is iltered off and crystallized from a mixture o 2,2'~oxybispropane and 2-propanol, yieldins 31.7 parts of 3-~ 4,5 dic~loro-2-nitrophenyl~amin ~ -1-propanol; mp.
97C.

.

.
.. .

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

~ ~7 Similarly were prepared:

3~ nitro-4-(trifluoromethyl)pheny ~ amino~-1-propanol;
and 2-~ -nitro-4-(trifluoromethyl)pheny ~ amino~ethanol;
mp. 74.9C.

Exam~e~

To a stirred mixture of 3g.2 p2rts of 3-(2-nitro-phenyl)amino-1-propanol and 225 parts of trichloro-methane are added dropwise 35.7 parts o~ sul~inyl chloride (exothermic reaction: temperature rises to 45C). Upon completion, stirring is continued ~or 6 hours at reflux temperature. The reaction mixture is evaporated, yielding 43 parts (100%) of N (3-chloro-propyl)-2-nitrobenzenamine as a residue.

SImilarly were prepared:

N-(3-chloropropyl)-2-nitro 4~(tri~luoromethyl)benzenamine a5 a residue;

4,~-dichloro-N-(3-chloropropyl)-2-nitrobenzenamine; mp.
78C; and N-(2-chloroethyl)-2-nitro 4-(trifluoromethyl)benzenamine.
. ' ' ' .

,.
~54 - .
, X

7~6 Example XI

A mixture of 21.5 parts o~ N-(3-chloropropyl)-2-nitrobenzenamine, 22.68 parts o 1-(diphenylmethyl)-piperazine, 20 p ~ts of N,N-diethylethanamine and 180 parts of N,N-dimethylacetamide is stirred and heated for 6 hours at 100C~ The reaction mixture is evapo-rated and the residue is taken up in water. The oily product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from a mixture of 2-propanol, ethanol and 2,2'-oxybispropane. The produc~ is filtered off and dried, yielding 15.5 parts (36.9%) of 4-(diphenyl-methyl)-N-(2-nitrophenyl) 1-piperazinepropanamine hydrochloride; mp. 2280C.

Similarly were prepared:

N-(4,5-dichloro-2-nitrophenyl)-4-(diphenylmethyl)-1-piperazinepropanamine as a residue;

4-(diphenylmethyl)-N- ~ nitro-4-(trifluoromethyl)-phenyl~ piperazinepropanamine; mp. 113~7C; and 4-(diphenylmethyl)-N- ~-ni~ro-4-(trifluoromethyl)-pheny ~^1-piperazineethanamine; mpO 15~,1C.

Exam~le _XII

A mixture of 15 parts of 4-(diphenylmethyl)-N-(2-nitrophenyl)-1-piperazinepropan~mine hydrochloride in 160 parts o~ methanol is hydrogenated at normal pressure znd at room temperature with 5 parts of Raney-. . , ~

. ~ ' ~ ` ~
.

~7~

nickel catalyst. After the calculated amount of hydrogen is taken up, ~he ca~alyst is filtered off over hyflo and the filtrate is evaporated. The solid residue i5 crystal-lized from a mixtuxe of 2-propanol and 2,2'-oxybispro-pane. The product is filtered of and dried, yielding 12 parts (78.~%) o~ N-(2-aminophenyl)-4-(diphenylmethyl)_ 1-piperazinepropanamine hydrochloride; mp. 223.1C.

Similarly were prepared:

4,5-dichloro~N1-~3- ~ -(diphenylmethyl)-1-piperazinyl~-propyl}-1,2-benzenediamine as an oily residue N1-¦3- C-(diphenylmethyl)-1-piperaziny ~propyl}-4-(trifluoromethyl)-1,2-benzenediamine; and N1-~2- C-(diphenylmethylj-l-piperaziny ~ ethyl~-4-(tri-fluoromethyl)-1,2-benzenediamine as an oily residue.

Example XIII --A mixture of 60.5 parts of 1-(3-chloropropyl)-1,3-dihydro-3-(1-methyleth nyl)-2H-benzimidazol-2-one, 31~68 parts of 1-(phenylmethyl)piperazine, 2102 parts of sodium carbonate, 001 parts of potassium iodide and 400 parts of 4 methyl-2-pentanone is stirred and refluxed . `

, _ ~

' .
.

~7 ~ ~

~or 20 hours ~ith ~ater-separator. The reaction mixture is cooled, water is added and the layers are separated.
The organic phase is dried, ~iltered and evaporated, yielding 70 parts (100%) o~ 1,3-dihydro-1-(1-methyl-ethenyl)-3-~3- r -(phenylmethyl)-1-piperaziny ~ propyl~-2H-benzimidazol-2-one as a residue.

Similarly was prepared 1,3-dihyd~o~ 2-~4-(pheny~
methyl)~1-piperazinyl~ethyl~ 2H benzimidaæol-2-one;
mp. 136.5C~

Exam~le XIV
.
To a stirred solution o~ 70 parts of 1,3-dihydro-1-(1-methylethenyl)-3- 13- ~4-(phenylmethyl)-1-piperazinyl~-propyl~-2H-benzimidazol-2-one in 240 parts o~ ethanol are added 55 parts o~ hydrochloric acid solution 6N.
The whole is stirred ~or 2 hours at 40-50C. The reaction mixture is evaporated and the residue is ~a~en up in a diluted ammonium hydroxlde solution. The oily product is OEtrac~ed with tricnloromethane. The extrac~ is dried, iltered and evaporated, yielding 63 parts (100%) o~
1,3 dihydro~ 3-~4-~phenylmethy~ piperaziny ~propyl~-2H-be~zimida~ol-2-one as a residue.

. ' ~ ~ ' r ., .

' ' ' ' ' ' ' ' ', Examp~e XV

A mixture of 63 parts of 1,3-dihydro~ 3-~4-(phenylmethyl)-1-piperazinyl~propyl}-2H-benzimida~ol-2-one in 400 p~r-ts of methanol is hydrogenated at nor-mal pressure and at room temperatul~e with 10 parts of palladium-on-charcoal catalyst 10%. A~ter the calcu-lated amount of hydrogen is taken up, the catalyst is filtered of~ cver hyflo and the filtrate is evaporated.
The residue is crystallized ~rom a mixture of 4-methyl-2-pentanone and 2-propanol. The product is Æiltered off and dried, yielding 29.5 parts (63%) 0~ 1,3-dihydro~ piperazinyl)propy ~ -2H-benz-imidazol-2-one; mp. 157.5C.

Similarly was prepared:

1,3-dihydro~ piperazinyl)ethy ~ -~H-benzimidzzol-2-one; mp. 122.6C.

Example XVI

To a stirred mixture of 20 parts of aluminium chloride and 100 parts o~ fluorobenzene ~re added drop-wise 20.5 parts o~ 2,4-dichlorobenzoyl chloride. Upon completion7 the mixture is heated to reflux and stirred at re1ux ~emperature for 5 minutes. The reaction mixture is poured onto ~rushed ice and the produc~ is extracted wit~ oxy~isethane. The extract is dried and evaporated, yielding 30 parts o~
(2,4-dichlorGphenyl)(4-fluorophenyl)methanone as an oily residue~

-5~_ , .

Similarly was prepared:

(4-~luorophenyl) (4-pyridinyl)methanone; mp. 85.5OC.

Example XVII

To a stirred and re~luxing mixture of 23.~ parts of (4-chlorophenyl)(2-~luorophenyl)methanone in 280 parts o~ 2-propanol are added portion~ise 3~7 parts of sodium borohydride. Upon completion, stirring is con-~inued for 2 hours at reflux temperature (+ 80~C~. The reaction mixture is cooled and decomposed by the ~ddition o~ water. The 2-propanol is evaporated and the residual product is extracted with trichloro-methane. The extract is dried, iltered and eva-porated, yielding 23.6 parts of 4-chloro~ -(2 ~luorophenyl)benzenemethanol as a residùe.

5imilarly were prepared:

2,4-dichloro~ -(4-fluorophenyl)ben~enemethanol as a residue;

~-~-Pluorophenyl)-~p~ridinemethanol; mp. 138.2C.

~-~4-1uorophenyl~-3-pyridinemethanol hydrochloride;
mp. 1S8.3C; and 4-metho~y~ (trifluoromethyl)phenyl~benzenemethanol as a residue.

' . ~ . .
., ~ .
~ ~ . .i . .

Example XVIII

A mixture o~ 22 parts of 2,4-dichloro~ -(4-fluoro-phenyl)benzenemethanol and 240 parts o~ hydrochloric acid solution 12N is stirred for 40 hours at room tempera-ture~ The reaction mixture is poured onto ice-water and the product is extracted with trichloromethane. The ex-tract is washed with water, dried, filtered and eva-porated. The residue is distilled, yielding 13.2 parts of 2,4-dichloro-1-~ hloro (4-fluorophenyl)methy~ benzene;
bp. 146C at 0.15 mm. pressure.

~ Similarly were prepared:

~ chloro-~-(4-methoxyphenyl)methyl~-3-(trifluoro-methyl)benzene as a residue; and 1~ hloro-(4-methylphenyl)methy ~ -4-1uorobenzene as a residue.

Example XIX
:
To a stirred mixture of 23.6 parts of 4-chloro ~ -(2 ~luorophenyl)benzenemethanol in 108 pa~ts of benzene are added dropwise 24 parts of sulfinyl chloride. Upon completion, the whole is heated to reflux and stirring is conti~ued first for 5 hours at reflux temperature and urther overnight at room temperature. The benzene is e~aporated and the residue is distilled, yielding 16~5 parts of 1-chloro-4-~ -chloro-~-(2-fluorophenyl)-methyl~benzene; bp. 122~125C at 0.1 mm. pressure.

-60;
. .

, ~ ~ 7 Similarly were prepared:

3-~ -chloro-~-(4-~luorophenyl)methyl~pyridine hydro-chloride as an oily residue;

3-~ -chloro-~-(4-chlorophenyl)methyl~pyridine hydro-chloride as a residue;

4-~ -chloro~~-(4-~luorophenyl)methy ~pyridine hydro-chloride; mp. 198-200C;

1-(chlorophenylmethyl)-2,3-dimethylbenzene; bp.
137C at 0.7 mm~ pressure;

1-(chlorophenylmethyl)-2,4~dimethylbenzene; bp~
137C at 0.7 mm. press~re;

2-(chlorophenylmethyl)-194-dimethylbenzene; bp.
136C at 0.7 mm. pressure;

1-(chlorophenylmethyl)-2-fluorobenzene; bp. 108-109C at 0.4 mm. pressure;

Example XX

A mixture of 121 parts of piperazine9 54 parts o~ 3-~ -chloro~ -(4-chlorophenyl)methy ~pyridine hydro-chloride and 315 parts of N9N-dimethylform~mide is stirred ~or 20 hcurs at room temperature. The reac~ion mixture is evaporated and 250 parts of wa~er are added to the residue. The produc~ is extracted with methyl-.... .
~61-~,,r _ , ~ ~7 ~ ~

benzene. The organic phase is washed wi-th water and extracted with an acetic acid solution 10%. The acid aqueous phase is alkalized with a sodium hydroxide solution 60% and the product is extracted again with methylbenzene. The extract is dried t filtered and e~a-porated. The oily residue is converted into the nitrate salt in ethanol. The salt is ~iltered o~, washed with ethanol and with 2,2'-oxybispropane and crystallized from ethanol, yielding 48 parts o~ -(4-chlorophenyl)-q -(3-pyridinyl)methy ~ piperazine trinitrate, mp. 132.9C.
.

Similarly ~ere prepared:

4-chlorophenyl)- ~-(2-~luorophenyl)methy ~ piperazine;

~ (4-fluorophenyl)~ (4-pyridinyl)methyl~piperazine;
mp. 108.4C; XLIII-1 -chlorophenyl)(3~chlorophenyl)methy ~ piperazine;

1-~ 2-fluorophenyl)phenylmethy ~ piperazlne ethanedioate (1:1); mp. 195.5C;

1-~ 4~1uorophenyl)(4-methoxyphenyl)methy ~ piperazine ethanedioate (1:2); mp. 280.1 C; and 1-~ 4-nitrophenyl)phenylmethyl~piperazine dihydro-chloride.

.
" ~ , , .

64~

Example XXI

A mixture of 21. 5 parts o~ ethyl 4-hydroxy-1-piperidinecarboxylate~ 35.2 parts of bis(4-fluoro-phenyl)bromomethane and 80 6 parts of potassium car-bonate is stirred and heated in an oil-bath at 140C
for 3 hours. The reaction mixture is allowed to cool to room temperature and water is added. The product is extracted with methylbenzene. The extract is was-hed successively with water, a diluted hydrochloric acid solution and a sodium bicarbonate solution, dried, filtered and evaporated. The forerun is distilled ~ f (bpo till 143~C at 0.5-1 mm. pressure) 7 yielding 29 parts of ethyl 4- ~ is(4-fluorophenyl~metho ~ -1-piperidinecarboxylate as an oily residue.

Similarly ~as prepared:

ethyl 4-(diph~nylmethoxy)-1-piperidinecarboxylate;
bp. 150C at 004 mmO pressure.

., A mixture of 29 parts o ~thyl 4 ris(4 fluoro-phenyl)metho ~ 1 piperidinecarboxylate, 25 parts of potassium hydroxide, 1 part of wa~er and 160 parts of 2~propanol i5 s~irred and xefluxed for 4 hours~ The solv~nt is evaporated and wa~er is added to the residue.
The product is extracted with methylbenzene. The extraci is ~ashed a ~ew times with water, dried~ ~iltéred and evaporated7 The oily residue is converted in~o the hydro-chloride salt in 4-methyl~2-pen~anone and 2-propanol at room temperature. The salt i5 filtered off and dried, yielding 200 5 parts (78%) of 4-~bis(4-fluorophenyl)-methoxy~piperidine hydrochloride; mp. 161.8C.

.~ .

~7~$

Similarly was prepared:

4-(diphenylmethoxy)piperidine hydrochloride; mp.
20g~80c.
, Example_ XXIII
-A mixture of 5.3 parts o~ 1-(3 chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one, 5 parts of 1-(diphenyl-methyl)piperazine, 6.4 parts of sodium carbonate and 200 parts of 4-methyl-2-pentanone is stirred and re~luxed overnight with water~separatorD After cooling, water is added and the layers are separated. The 4-methyl-2-pentanone-phase is dried, filtered and evaporated. The residue is puri~ied by col~n-chromatography over sili-ca gel using a mixture o~ trichloromethane znd 5% o methanol as eluent. The pure fractions are collected and the eluen~ is evaporated. The oily residue is crystallized ~rom a mixture o~ 2,2'-oxybispropane a~d a s~all amount of 2-propanol. The product is fi~tered of and dried, yielding 2 parts (23%) Of 1-~3- ~ -(diphenylmethyl3-1-piperazinyl~propyl}-1,3-dihydro-2H-benzimidazol 2-one;
mp. 153.6~C~
, In a similar manner the ~ollowing compounds ~ere prepared in free base ~orm or in the ~orm of an acid addition salt after treatment o~ the ~ree base with an appropriate acid:

~64-:
~ . , 6~i I , , : ~
c~
o U~ O ~D I
~ ~o~ 0~ !
. .
~ ... ~ ----- I
o~ I
o I
~, o ~
~3 ,a ,Q O ~ R R ~ .a ,a rQ .a ,4 ~
''............... I~ . I
Z; _ ..
- - -,, ~ ~ ~ ~ ~
,~z ~ c`~ ~ ~ x~ ~ l v v v o O ~ K ¢ t~ V I L ~D V~ C~`` V~ V~D ~ V

_ .. ..... _ .,.. ,~ _ ..... .... _.______ I

U~ ~ V ~ U~ U~ Lr~ V V
¢ ~ X ~
~ ~ V~ ~ V~D V~ I I 1 1 --~

~ v v v v v v ~) v v v v v v v !
. ~ _ ~
~ ,~
' ~ V~
U~ X ~ ~ I
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V
V V
. . '' '' 'I
_ ~
..

: b5-~ . ,.
~ .

~ Cg7~j;4~

. . . ~ _ ., ~ t O ~ ~ ~ ~
va~ O O . a~ ~ ) o u~00 i b)o ~ C`l C~ ~ ~ ~ ~ , .,, ~
., ~:
o ~ :C~ o ' - ~ ' f~ ~ ~ ~ ~ ~ v ~
o o tn u~
aJ ~ ,C~ 5V . ~ ~

. _ . . I

3~ ~ I

C.~ V ~ ~ ~ ~ O ~f ~ I h ~ ~ '~
e3 ~ 3 V 5U~ J
~ V~ V~
_ ~

V {~ - I

o ~ ~
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u ~ v -~

6 6 ~

.

~7 - ... .

po~
b) CJ~
~ C~ C~i .,. ~ , ~: ~ .
, h .
O O
4~ o ~ , ~Cuo~
C~
5~ ~
~ . .C~ Ul U) ~ , U~
~ ~ U) oh ~ ~ ~ ~
a a~
, ., ~ ' ~U~
¢ V~O I
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~ t.) V
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~_ ~ ' S~D ~ ~
~ v~) _ ~_____ C'~
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C~l C~
. ~ ~ ~ C7 V
C~ ~
. ~ ._ _ . ,.
V ~
~ ~ C
_ ~ _ ~.

~:1 : R ~ ~

.'~;. `

Exam~e XXIV

In an analogous manner as described in Example XXIII there were prepared:

~ 4-~ is(4-fluorophenyl)methyl~-1-piperazinyl~-propy ~1,3-dihydro-2H-benzimidazol-2-one; mp.
197.3C by the reaction of 1,3-dihydro-1-(3-hydroxy-propyl)-2H-benzimidazol-2-one methanesulfonate with 1-~ is(4~fluorophenyl)methylJpiperazine;

1-~3-~ -(diphenylmethyl)-1-piperaziny ~propyl~ 1,3-dihydro-3-methyl-2H-benzimidazol-2-one dihydro-chloride hydrate; mp. 201,8C by the reaction of 1,3-dihydro-1-(3-iodopropyl)-3-methyl-2H-benz-imidazol-2-one with 1-(diphenylmethyl)piperazine;

3-~3-~ -(diphenylmethyl) 1-piperaæinyl~propyl~-2(3H)-benzothiazolone dihydrochloride. hemihydrate;
mp. 186.1C by the reaction of 3-(3-bromopropyl)-2(3H)-benzothiazolone with 1-(diphenylmethyl)-piperazine; and 3-13-~ -(diphenylmethyl)-1-piperazinyl~propyl~-2(3H)-benzoxaz~lone dihydrochlo~ide; mp. 212.4C
~y the reaction of 3-(3-chloropropyl)-2(3H)-benzo-xazolo~e with 1-(diphe~ylmethyl)piperazineO

Example XXV

A mixture of 6.95 par~s o~ 1~(5-chlorope~tyl)-1,3 dihydro-3~ methylethenyl)~2H-benzimidazol-2-onet 5.15 parts of 1-(diphenylmethyl)piperazine, 5.30 par~s of sodium car~onate, 0.1 parts of potas-sium iodide ~nd 16Q parts of 4-methyl-2-pentanone is 6 8 ~

. . . . .

~`~Q7~4~

stirred and refluxed ~vernight with wa~er-separator.
The reaction mixture is cooled to room temperature, water is added and the layers are separated. The organic phase is dried, ~iltered and evaporated. The residue is stirred and re~luxed ~or 30 minutes with 12 parts of a hydrochloric acid solution in 40 parts o ethanol. The whole is evaporated and the residue is crystallized from ethanol, yielding 5 parts (46%) o 1- ~5-~ -(diphenylmethyl)-1-piperaziny ~pentyl~-1,3-dihydro-2H-benzimidazol-2-one dihydrochloride hydrate;
mp. 215.3C.
.

Similarly ~ere prepared: Ar1 7~~ ( CH2 ) n~N~N~CH

n - - L ~2 , 3 =elor ~ ~ ~ c 4~F-C6H4 4-F-C6H42HGl.H20 2~3.7 4 C6H5 4-F-C6H4 base 172.3 3 C~H5 2-Cl-G6Hbase 149 3 3-Cl-C6H4 2-Cl~C6H4 base.H20 13901 3 C6H5 2~4-Cl2- base 160.1 6 C6H5 C6H5 base 189.7 6 4-F-C6H~ 4-F-C6H42HCl 204.5 X ' '', ~L [3?~7~

Example XXVI

To a s~irred solution of 76 parts o~ 3-~ -(diphenylmethyl)-1~piperazinyl7propyl~-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-one in 280 parts of ethanol are added 120 parts o~ hydrochloric acid solution and 250 parts of water. The whole is stirred for 30 minutes a~ room temperature. Upon cooling in an ice bath, the product is precipitated. It is filtered of, washed with 2-propanone and wi~h 2,2'-oxybis-propane, and dried, yielding 43 parts (55%~ of 1-~3- ~ -(diphenylmethyl)-1-piperaziny ~propyl~-1,3-di-hydro-2H-benzimidazol-2-one dihydrochloride hydrat~;
mp. 237.5C.

Similarly ~ere prepared:

HN'~`M-C ~2 ~N N-CH 2 4 ~ 7 _ _ ~ 2 mp. ~
R CnH2n . Ar ~r in _ _ ___ H (CH2)3 3-pyridinyl 4-Cl-C6~4 l60.2 H (CH2)3 4-pyridinyl 4-F-C6H~ 183.2 H (CH2)3 4-Cl-C6H4 4 3 ~6H4 199.3 H (CH2)3 C6H5 2-F-C6H4 157.7 5-CH3 ~CH2)3 C6H5 C6H5 178.3 6-CH3 (~H2)3 C~H5 ~6H5 195.7 N ~N_-OH(~ 4~ 4 - r - c ~- 4 176 -70~ -., ~, 7~

Example XXVII

A mixture of 3.6 parts o~ N1-¦2-~4-(diphenyl-methyl)-1~pipera2iny ~ e~hyl~-4-(tri1uoromethyl)-1~ -benzenediamine and 1.8 parts o~ urea is stirred for 3 hours in an oil;bath at 190C. The reaction mixture is cooled, water and trichloromethane are added and the layers are separated. The organic phase is dried, filtered and evaporatedO The residue is purified by column-chromatography over silica gel using a mixture o trichloromethane and methanol (95:5) as eluent. The pure Practions are collected and the eluent is evaporated, yielding 1~5 parts ! (41.5%) of 1-~2-~4-(diphenylmethyl)-1-piperazinyl~ -ethyl}-1,3-dihydro-5-(trifluoromethyl)-2H-ben~imida-zol-2-one; mp. 163~7C.

Similarly ~ere prepared:
.
1-~3-~4 (diphenylmethyl)-1 -piperazinyl~propyl~ -1, 3-dihydro-5-(trifluoromethyl3-2H-benzimidazol-2-one;
mp. 152.7C; and 5,6-dichloro~ 3- r -~diphenylmethyl)-1-pipe~aziny ~-propyl~-1,3-dihydro-2H-benzlmidazol-2 one; mp. 214.~C.

Example XX~III .

A mixture o~ 2.3 parts o~ 3-~ -(diphenylmethyl)-1-piperazinyl~propyl}-1, 3-dihydro-2H-benzimidazol-2-one, 405 parts of ormaldehyde solution 40% and 45 parts Ot N,N~dimethylformamide is stirred and heated for 2 hours at 100C. The reaction mixture is cooled and diluted with -71_ .

$~

water. The precipitated product is filtered off and crystallized from methylbenzene, yielding, a~ter drying, 1~5 parts (66%) of 1-~3-~4-(diphenylmethyl)-1-pipe~azinyl~ -propyl}-1,3-dihydro-3-(hydroxymethyl)-2H-benzimidazol-2-one; mp. 102.5C.

Example XXIX

A mixture of 1.55 parts oP acetic acid anhydride, 3 parts of 1-l3-~ -(diphenylmethyl)~1-piperaziny ~propyl~-1,3-dihydro-2H-benzimidazol-2-one and 22.5 parts o~
methylbenzene is stirred and refluxed overnight. Water is added to the reaction mixture and the layers are separated. The organic phase is dried, Eiltered and evaporated. The residue is puriied by column-chromato-graphy over silica gel using a mixture of trichloromethane and methanol (~5:5) as eluent~ The p~re fractions are collected and the eluent is evaporated, yielding 1~1 parts (33.5%) of 1-acetyl~3~3-~ -(diphenylm thyl)-1-piperazinyl~propyl}-193-dihydro-2H-benzimidazol 2-one;
mp~ 124.4C~

A mixture of 101 parts of ethyl 2-propenoate, 3 parts of 1-~3-~ -(diphenylmethyl) 1-piperaziny ~propyl~-1,3;dihydro-2H-benzimidazol-2-one, a ,ew drops o~ ~,N,N-trimethylbenzenemethanaminium hydroxide solution 40% in methanol and 25 parts of 1,4~dioxane is s~irred and re-fluxed for 24 hours. The reaction mixture is evaporated.

' ' ~ 7 ~

The residue is purified by column-chromatography over silica gel using a mixture of trichloro-methane and methanol (95:5 ) as eluent. The pure fractions are collected and the eluent is evapo-rated. The residue is converted into the hydro-chloride salt in 2~propanol and ethanol. The salt is ~iltered off and dried, yielding 1.4 parts (32.5%) o~ ethyl 3-13- ~ -(diphenylmechyl)-1-piperazinyl~propyl~ -2,3-dihydro-2-oxo-1H-benz-imidazole-1-propan~ate dihydrochloride. dihydrate;
mp. 204C.

Example XXXI

A mixture of 3 parts of 1- ~- C -(diphenyl-methyl)-1-piperaziny ~ propyl}-1j3-dihydro-2H-benz~
imidazol 2 one t 1 part of isocyanatomethane and 25 parts of 1,4-dioxane is stirred and re~luxed overnight. The reaction mixture is evaporated and the residue is puri~ied by column-chromato~raphy over silica gel using a mixture of t~ichloromethane ~nd methanol (95:5) as eluent. The pure fractions are collected and the eluent is evaporated. The residue i5 crystallized from a mixture of methyl-benzene and 2,2'-oxybispropane, yielding 0~8 pa~ts (23.5%) o~ 3~ (diphenylmethyl)-1-piperaziny ~ -propyl~-2,3-dihydro-N;methyl-2-oxo-1~-benzImidazole-1-carboxamide; mp~ 153.1C~

xample XXXII

To a stirred mixture of 9~4 parts of 1-~3- ~ -~diphenylmethyl3-1-piperazinyl~propyl~-1,3~dihydro-2H-benzimidazol-2-one and 180 parts o~ methylbenzene -- .
,~, , .

~ 7~ ~

are added 0.8 parts o~ sodium hydride dispersion 75% and the whole is stirred and heated ~or 60 minutes at 90C.
After cooling to 30C, 0.2 parts of 2,3,11,12-dibenzo-1,4,7,10,13,16-hexaoxacyclooctadeca-2,11-diene are added and stirring is continued ~or 10 minutes. Then there are added 4.2 parts of ethyl 2-bromoacetate and the mixture is stirred and refluxed overnight.
The ~eaction mixture is cooled to 90C, 50 parts o~ water are added and the layers are separated while hot. The organic phase is evaporated, yielding 10 parts o ethyl 3-~3-~4-(diphenylmethyl)-1-piperazinyl~-propyl}-2,3-dihydro-2-oxo-1H-benzimidazo~ acetate as a residue.
.
A mixture of 9.8 parts of ethyl 3-~3-~ -(diphenyl-methyl)-1-piperazinyl~propyl~-2~3-dihydro-2-oxo-1H- -benzimidazole-1-acetate, 1.2 parts oE sodium hydroxide and 150 parts o~ water is stirred and refluxed for 5 minutes (+ 80C). The reaction mixture is iltered and the filtrate is acidiied with acetic acid to pH 5.8-6: a sticky precipitate is formed. It is separated and crystallized ~rom ethanol and water. The product is ~iltered o~f and dried in ~acuo at 100C for 3 hours, yielding 6 parts of 3-{3- ~-(diphenylmethyl)-1-pipera-ziny ~propyl~-2 9 3-dihydro-2-oxo-1H henzimidazole 1-acetic acid hemihydrate; mp~ 138.7C.

Example XXXIII

~ mixture of 5.2 parts o~ 1,3-dihydro~1- C -(1-piperazinyl3propyl~ -2H-benzimidazol-2-one, 5.28 parts of 2-~chlorophenylmethyl)pyridine hydrochloride, 5.3 parts of sodium carbonate and 90 p~rts of N,N-dimethyl-formamide is stirred and heated overnight at 50~C. The reaction mixture is cooled and poured on~o ice-water.

9~n7~

The product is extracted with methylbenzene. The extract is dried, filtered and evaporated. The residue is crystallized from a mixt~re of 4-methyl-2-pentanone and 2,2' oxybispropane. The product is filtered off and dried, yielding 2 parts (23.4%) of 1,3-dihydro-1-- ~- ~ henyl(2-pyridinyl)methy ~ ~1-piperazinyl}propy ~-2H-ben~imidazol-2-one; mp. 141.7C.

Similarly ~ere prepared:

~--(CH2)3--N~N_CII

_ _ Ar1 A~2 mp. in C
. _ _ 3-pyridinyl4-F-C6H4 154.1 3~pyridinyl C6H5 162.6 4-F-C~H4 4-CH3-C6H4 147.8 .
4-Cl~C6H44-Cl-C6H4 209.5 4-F-C6H42,4 Cl2 C6H3 160.1 C6H5 C6H3 169.8 3 3 6 44~ 3 6 4 153.4 C6H5 4 3 6 4 178~3 C6H5 ~6H3 115~8 2~ ~OC~U)~-.

' ' ' ~

, ~7~L

Example XXXIV

A mixture o~ 4.9 parts o 1-(3-chloropropyl)-1H-benzimidazol~ 5.76 parts of 1-~ is(4-fluoro-phenyl)methy ~ piperazine, 5.3 parts of sodium carbonate, 0.1 parts o potassium iodide and 200 parts of 4-methyl-2-pentanone is stirred and re-~luxed ~or 20 hours with water-separator. The reaction mixture is cooled, water is added and the layers are separated. The organic phase is dried, filtered and evaporated~ The residue is crystallized from a mixture of 4-methyl-2~p~ntanone and 2,2'-oxy-bispropane~ The product is filtered off and dried, yielding 5.5 parts (59.3~) o 1~ 4-~bis(4-fluorophenyl)methy ~ -1-piperazinyl}propy ~ -1H-benz-imidazole hydra~e; mp. 108.4C.
. .

. .
Similarly ~ere prepared:

nH2n~N~ N-cH

5 Rl ~

.~ ~, ' .
. ., " ..
.: ,. - - ~ , ~ .

~7~

_ I
.~ , .
c~
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r 7 6 ~6 Example XX~V

Following the procedure o~ Example XXIV there is prepared 1-~3-~4-(diphenylmethyl)-1-piperazin propyl}-2-(methylthio) lH-benzimidazole trihydro-chloride. hydrate; mp. 203.4C by the reaction of 3-~2-(methylthio)-1H-benzimida~ol-1-y ~ propyl methane-sulonate with 1-(diphenylme~hyl)piperazine.
.

Example XXXVI

A mixture of 4.37 parts of N~(2-aminophenyl)-4-(diphenylmethyl)-1-pipera~inepropanamine hydrochloride, 38 parts of carbon disulfide, 2 parts of sodium car-bonate and 40 parts of ethanol is stirred and refluxed for 20 hours. The reaction mixture is evaporated and water is added to the residue. The precipitated product is ~iltered of~, ~ashed with water and dissol~ed in trichloromethane. The solution is dried, filtered and evaporated, The residue is crystallized from 4-methyl-2-pen~anone, yielding ~ parts (45~5~O) of 1-~3- ~ -(diphenyl-methyl)-1-piperazinyl3propyl}-1~3-dihydro-2H-benzimida-zole-2-thione; mp. 1810 a ~c.

~39e~le X~r -A mixtuxe of 60 parts of N (2~aminophenyl)-4-(di-phenylmethyl)-1-piperazinepropanamine, 20 parts of methyl (iminomethoxymethyl)carbamate, 42 par-s o~ -acetic~acid and 450 p æts of trichloromethane is stirred and refluxed overnight. The reaction mixture is eva-porated and the residue is stirred in water. The latter is . .

-80- ~

' , ~7~

decanted and the residue is taken up again in water.
The whole i5 alkalized ~ith a diluted ammonium hydroxide solution and the product is extracted with trichloro-methane. The extract is dried, iltered and evaporated.
The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane, yielding 13.5 parts of methyl ~-~3-~4-(diphenylmethyl)-1-piperaziny ~ propyl~-1H-benzimidazol~2~y ~carbama~e; mp. 137.8C.

A mixture o~ 12 parts of methyl ~-{3- ~ -(diphenyl-methyl)~1-piperazinyl~propyl~-1H-benzimidazol-2-y ~-carbamate, 60 parts of a concentrated hydrochloric acid solution and 80 parts of ethanol is stirred and refluxed overnight. The reaction mixture is evaporated and water is added to the residue. The free base is liberated in the conventional manner with ammonium hydroxide and extracted wi~h trichloromethane. The extract is dried, ~iltered and evaporated. The residue is crystalli7ed ~rom ethanol~ The product is ~iltered o~ and dried, yieldin~ 4~3 parts (40%) of 1-{3-~4-(diphenylmethyl)-1~piperazinyl~propyl~-lH~benzimidazol-2-amine; mp.
228O70C.
., . . : ~
A mixture of 10.7 parts o~ 3-~4-~diphenylmethyl)-1-piperazinyl~propyll-~H-benzimidazol 2-amine 9 5.1 parts o~ acetic acid anhydride and 90 parts of methylbenzene is stirred and re~luxed for 5 hours. The reaction mixture is evaporated and the residue is stirred in water. The whole is al~alized with a~monium hydxo-xide and the product is extracted wi~h trichloro-methane. The extract is dried, filtered and eva-- porated. The residue is crystallized ~rom ethanol.

~81 :

7~6 The product is ~iltered off and dried, yielding 6.6 parts (56.5%) o~ N~ 3- ~-(diphenylmethyl)-1-piperaziny ~propyl~-1,3~dihydro-2H-benzimidazol-2-ylidene acetamide; mp. 143~3C.

Example XX~VIII

A mixture of 13 parts o 1,3-dihydro-1- r-(1-piperazinyl)propy ~-2H-benzimidazol-2-one, 12.4 par~s o~ 1,1'-(bromomethylene)bis ~ enzen~ , 6.6 parts of sodium carbonate and 200 parts of 4-methyl-2-pentanone is stirred and refluxed overnight with water-separa- -tor. A~ter cooling to room temperaturP, water is ad~ed and the layers are separated. The organic layer is dried, filtered and evaporated. The residue is crystallized ~rom a mixture o~ 2,2' oxybispropane and a small amount of 2-propanol, yielding 1-~3- ~ -(di-phenylmethyl)-1-piperaziny ~ propy~ -1,3-dihydro-2~-benzimidazol-2-one, mp. 153Co .
':

. ~ .
Following the procedure o~ Example XX~III and using equi~alent amounts o the appropriate starting materials, the ~ollowing compounds are prepared:

~ 4-~bis(4-~luorophenyl)methylJ-1 piperazinyl}~
ethy ~ -1,3-dihydro-2H~benzimidazol-2-one hemi-hydrate; mpO 131~5C, 1-~2- ~ -(diphenylmethyl)-1-piperaziny ~ ethyl~-1,3-dihydro-2H benzimidazol-2-one 9 mp. 218 4 C; and 0~ , 7~

~ 4-~bis(4-fluorophenyl)methyl~-1-piperazinyl}-propy ~ -1,3-dihydro~2H-benzimidazol-2-one; mp.
198C.

Example XL

A mixture of 4.8 parts of 1-(3-chloropropyl) 1,3-dihydro-2H-benzimidazol-2-one, 6.1 parts of 4-(diphenylmethoxy)piperidine hydrochloride, 7.5 parts o sodium carbonate and 200 parts of 4-methyl-2-pentanone is stirred and refluxed overnight with ~ater-separator. The reaction mixture is cooled and water is added. The layers are separated and the 4-methyl-2-pentanone-phase is dried, ~iltered and evaporatedO The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 5% of methanol as eluent. The pure fractions are collected a~d the eluent is ev~-porated. The residue is crystallized ~rom 4-methyl-2-pentanone, yielding 4.2 parts (48%) of 1-~3~ ~ -~diphenylmethoxy) 1-piperidiny ~propyl}-1,3-dihydro-2H-benzimidazol-2-one; mp. 149. 2Co . . .

Simil~rly were prepared:

~ . .

~l$~7646 B ( CH2 ) n N~}O-CH

Base or mp.
B n Ar Ar Salt form in ~ ~ _ , N _ 2 C6H5 C6H5 HCl 253~1 1 3 4-F-C6H4 4-F-C6H4 HCH2/2 167.2 ¦ ¦ 2 ~4-F-C6H4 ~4-F-C6~4~HCl 1/2 ~2 1.4~ :

n 4 C6H5 G6H5 base 152 .

b3se 11 .2 ..

~, 1'~ ._

Claims (16)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for preparing a chemical compound selected from the group consisting of a compound having the formula (r) and the pharmaceutically acceptable acid addition salts thereof, wherein:
Ar1 and Ar2 are each independently selected from the group con-sisting of phenyl, substituted phenyl and pyridinyl, wherein said substituted phenyl is phenyl having from 1 to 2 substituents independently selected from the group consisting of halo, lower alkyl, lower alkyloxy trifluoromethyl and nitro;
m is the integer zero or 1;

A is a member selected from the group consisting of and , provided that when said A is then said m is zero and when said A is then said m is 1;

n is an integer of from 2 to 6 inclusive, provided that when CnH2n represents a branched alkylene chain, then at least 2 carbon atoms are present in the linear portion of the chain linking B with the piperidine or piperazine nitrogen atom; and B is a member selected from the group consisting of:
a) a radical having the formula wherein:
R1 and R2 are each independently selected from the group consisting of hydrogen, halo, lower alkyl and trifluoromethyl; and Y is a member selected from the group consisting of oxygen, sulfur and a substituted nitrogen of the formula wherein said L is a member selected from the group consisting of hydrogen, lower alkyl, lower alkylcarbonyl, lower alkyloxycarbonyl-lower alkyl r carboxy-lower alkyl, phenyl, phenylmethyl, lower alkylaminocarbonyl, hydroxy-methyl, and lower alkenyl; and b) a radical having the formula wherein:

R1 and R2 are each independently selected from the group consist-ing of hydrogen, halo, lower alkyl and trifluoromethyl; and M is a member selected from the group consisting of hydrogen, lower alkyl, phenyl, phenylmethyl, mercapto, lower alkylthio, amino, lower alkylcarbonylamino, lower alkyloxycarbonylamino, and cycloalkyl having from 3 to 6 carbon atoms, characterized by a) reacting a reactive ester of the formula B' -CnH2n-W
wherein B' is the same as B defined above but other than a 2-amino-1H-benzimidazol-l-yl radical of the formula and W is halo or a reactive ester function derived from the corresponding alcohol, with a compound of the formula (III) in the presence of a reaction-inert organic solvent and a base, and at elevated temperatures in order to prepare a compound of the formula (I') or b) decarboxylating a compound of the formula (I-b) under hydrolytic conditions, in order to prepare a compound of the formula (I-a) or c) ring closing a compound of the formula (IV) with a cyclizing agent in order to prepare a compound of the formula (I-c) or (I-d) wherein M' is hydrogen, lower alkyl, phenyl, phenylmethyl, mercapto, amino, lower alkyloxycarbonylamino or cycloalkyl, by the reaction of (IV) with a cyclizing agent, or d) removing a protecting group P
from a compound of the formula (V) in order to prepare a compound of the formula (I-c) said group P comprising lower alkyloxycarbonyl or a substituted ethenyl group of the formula where R3 and R4 may represent different groups but wherein R3 is preferably lower alkyl and R4 is preferably hydrogen, lower alkyl or phenyl;
when the protecting group is lower alkyloxycarbonyl, it may be removed by alkaline hydrolysis, and when the protecting group is a substituted ethenyl group it is eliminated by subjecting the intermediate (V) to acid hydrolysis, and in carrying out said acid hydrolysis to remove the substituted ethenyl group from (V) a wide variety to protonic acids may be employed, which include mineral acids selected from the group hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acid, and organic acids selected from the group acetic, propanoic, ethanedioic and effecting the reaction in reaction-inert organic solvents.

or e) acylating a compound of the formula (1-a) above, to prepare a compound of the formula (I-e) or f) introducing the group L1 into a compound of the formula (I-c) above, in order to prepare a compound of the formula (I-f) wherein L1 is selected from the group consisting of lower alkyl, lower alkylcarbonyl, lower alkyloxycarbonyl-lower alkyl, carboxy-lower alkyl, phenylmethyl, lower alkylaminocarbonyl, hydroxymethyl and lower alkenyl, provided that the unsaturation in said lower alkenyl is located in a position other than d, or g) condensing a compound of the formula (XVI) with a reactive ester of the formula (XVII) wherein W is defined hereinabove, in the presence of a reaction inert organic solvent and a base and at elevated temperatures, in order to prepare a compound of the formula (I-g) or h) preparing a compound of the formula (I-h) by S-alkylating procedures, starting from the corresponding -SH substituted analog; and, if desired, preparing pharmaceutically acceptable acid addition salts of the products of steps a) through h).

2. A process for preparing a chemical compound accord-ing to claim 1, selected from the group consisting of 1-{3[4-(diphenylmethyl)-1-piperazinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one and the pharmaceutically acceptable acid addition salts thereof, characterized by reacting 1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one with 1-(diphenylmethyl1piperazine and, if desired, preparing a pharmaceutically acceptable acid addition salt of the product thereof.

3. A process for preparing a chemical compound accord-ing to claim 1, selected from the group consisting of 1[3-{4-[bis(4-fluorophenyl)methyl]-1-piperzinyl}propyl]-1,3-dihydro-2H-benzimidazol-2-one and the pharmaceutically acceptable acid addition salts thereof, characterized by reacting1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one methanesulfonate with l-[bis(p-fluorophenyl)methyl]
piperazine and, if desired, preparing a pharmaceutically acceptable acid addition salt of the product thereof.

4. A process for preparing a chemical compound according to claim 1, selected from the groups consisting of 1-[4-{4-[bis(4-fluorophenyl)methyl]-l-piperazinyl}
butyl]-1,3-dihydro-2H-benzimidazol-2-one and the pharmaceutically acceptable acid addition salts thereof, characterized by reacting l-(4-chlorobutyl)-1,3-dihydro-2H-benzimidazol-2-one with l-[bis(p-fluorophenyl)methyl] piperazine, and, if desired, preparing a pharmaceutically acceptable acid addition salt of the product thereof.

5. A process for preparing a chemical compound according to claim 1, selected from the group consisting of 1-{4-[4-(diphenylmethyl)-l-piperazinyl}butyl}-1,3-dihydro-2H-benzimidazol-2-one and the pharmaceutically acceptable acid addi-tion salts thereof, characterized by reacting 1-(4-chlorobutyl) -1,3-dihydro-2H-benzimidazole-2-one with l-(diphenylmethyl) piperazine and, if desired, preparing a pharmaceutically accep-table acid addition salt of the pxoduct thereof.

6. A process for preparing a chemical compound accoxdiny to claim 1, selected from the group consisting of 1-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-lH-benzimidaæole and the pharmaceutically acceptable acid add.ition salts thereof, characterized by reacting 1-(3-chloropropyl)-lH-benzimidazole with l-(diphenylmethyl) piperazine.

7. A process for prepaxing a chemical compound accord-ing to claim 1, selected from the group consisting of 1-[4-{4-[(4-fluorophenyl)phenylmethyl]-1-piperazinyl butyl]-1H-benzimidazole and the pharmaceutically acceptable acid addition salts thereof, characterized by reacting 1-(4-chlorobutyl)-1H-benzimidazole with 1-[(4-fluoro-phenyl)phenylmethyl]plperazine, and, if desired, preparing a pharmaceutically acceptable acid addition salt of the product thereof.

8. A process for preparing a chemical compound according to claim 1, selected from the group consisting of 1-(4-{4-[bis(4-fluorophenyl)methyl]-1-piperazinyl}
butyl]-1H-benzimidazole and the pharmaceutically acceptable acid addition salts thereof, characterized by reacting 1-(4-chlorobutyl)-1H-benzimidazole with 1-[bistp-fluoro-phenyl)methyl]piperazine and, if desired, preparing a pharmaceutically acceptable acid addition salt of the product thereof.

9. A chemical compound selected from the group consist-ing of a compound having the formula (I) and the pharmaceutically acceptable acid addition salts thereof, wherein:
Ar1 and Ar2 are each independently selected from the group con-sisting of phenyl, substituted phenyl and pyridinyl, where-in said substituted phenyl is phenyl having from 1 to 2 substituents independently selected from the group con-sisting of halo, lower alkyl, lower alkyloxy trifluoromethyl and nitro;

m is the integer zero or 1;

A is a member selected from the group consisting of and provided that when said A is then said m is zero and when said A is then said m is 1;

n is an integer of from 2 to 6 inclusive, provided that when CnH2n represents a branched alkylene chain, then at least 2 carbon atoms are present in the linear portion of the chain linking B with the piperidine or piperazine nitrogen atom;
and B is a member selected from the group consisting of:
a) a radical having the formula wherein:

R1 and R2 are each independently selected from the group consisting of hydrogen, halo, lower alkyl and trifluoromethyl; and Y is a member selected from the group consisting of oxygen, sulfur and a substituted nitrogen of the formula wherein said L is a member selected from the group consisting of hydrogen, lower alkyl, lower alkylcarbonyl, lower alkyloxycarbonyl-lower alkyl, carboxy-lower alkyl, phenyl, phenylmethyl, lower alkylaminocarbonyl, hydroxy-methyl, and lower alkenyl; and b) a radical having the formula wherein:

R1 and R2 are each îndependently selected from the group consisting of hydrogen, halo, lower alkyl and trifluoromethyl; and M is a member selected from the group consisting of hydrogen, lower alkyl, phenyl, phenylmethyl, mercapto, lower alkylthio, amino, lower alkylcarbonylamino, lower alkyloxycarbonylamino, and cycloalkyl having from 3 to 6 carbon atoms whenever prepared or produced by the process of claim 1 or by any chemical equivalent thereof.

10. A chemical compound selected from the group consist-ing of 1-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one and the pharmaceutically acceptable acid addition salts thereof whenever prepared or produced by the process of claim 2 or by any chemical equivalent thereof.

11. A chemical compound selected from the group consist-ing of l-[3-{4-[bis(4-fluorophenyl)methyl]-1-piperazinyl}propyl}
-1,3-dihydro-2H-benzimidazol-2-one and the pharmaceutically accep-table acid addition salts thereof whenever prepared or produced by the process of claim 3 or by any chemical equivalent thereof.

12. A chemical compound selected from the group consist-ing of l-[4-{4-[bis(4-fluorophenyl)methyl]-l-piperazinyl}butyl]
-1,3-dihydro-2H-benzimidazol-2-one and the pharmaceutically accep-table acid addition salts thereof whenever prepared or produced by the process of claim 4 or by any chemical equivalent thereof.

13. A chemical compound selected from the group consisting of 1-{4-[4-(diphenylmethyl)-l-piperazinyl]butyl}-1,3-dihydro-2H-benzimidazol-2-one and the pharmaceutically acceptable acid addition salts thereof whenever prepared or produced by the process of claim 5 or by any chemical equivalent thereof.

14. A chemical compound selected from the group consist-ing of l-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-lH-benzimidazole and the pharmaceutically acceptable acid addition salts thereof whenever prepared or produced by the process of claim 6 or by any chemical equivalent thereof.

15. A chemical compound selected from the group consisting of 1-[4-{4-[bis(4-fluorophenyl)phanylmethyl]-1-piperazinyl}butyl]-lH-benzimidazole and the pharmaceutically acceptable acid addition salts thereof whenever prepared or produced by the process of claim 7 or by any chemical equivalent thereof.

16. A chemical compound selected from the group consisting of l-[4-{4-[bis(4-fluorophenyl)methyl]-1-piperazinyl}butyl]-lH-benzimidazole and the pharmaceutically acceptable acid addition salts thereof whenever prepared or produced by the process of claim 8 or by any chemical equivalent thereof.