Note: Descriptions are shown in the official language in which they were submitted.
S8~2
BACKGROUND OF THE INVENTION:
In the prior art there may be found a number of
benzazolylalkyl and indolylalkyl substituted piperidine deriva- -
tives and a number of aminoalkyl substituted benzazoles some of
them having pharmacological, e.g. antidepressant, anticon-
vulsant, antihistaminic or antispasmogenic activities.
Among other points of difference, the subject com-
pounds of this invention differ from such known compounds by
the na-ture of respectively the benzazole and/or substituted
piperidine moiety within their structure. ~-
A number of the aforementioned prior art compounds
may be found in the following references:
Int. Pharmacopsychiat. 1968 (1), p. 214;
C.A., 64 2093 b (1966);
C.A., _ 111466 (1970);
C.A., 81 120632 b (1974);
Fr. Pat. No. 2,042,321 (Derw. Fr. Week S16, Pharm.
p. 12); and
Belg. Pat. No. 753,472.
DESCRIPTION OF THE PREFERRED EMBODIMENTS:
The novel l-(benzazolylalkyl)piperidine derivatives
of this invention may structurally be represented by the fol
lowing formula:
....
.
R3
I ,
B~N_(CH2)n, Cl-l (c~l2)n-Nv
R R
and the pharmaceutically acceptable acid addition salts thereof,
whereln:
Rl and R are each independently selected rom l;he group consisting
of hydrogen, halo, lower alkyl and trifluoromethyl;
~ ,
B is a member selected from the group consisting of the bivalent ~-
~0 ~ ~0~ ,0
-N=CH-, said L being amember selected from the group ,~
consisting of hydrogen, lower alkyl, lower alkylcarbonyl and t~;
lower alkenyl, and said bivalent radicals being attached to
the ben~ene nucleus with their heteroatom;
R3 is a member selected from the group consisting of hydrogen and _~
~nethyl;
.,
m and n are each an integer of from 1 to 2 inclusiv~; and ~ '
the radical -N ;~ is a member selected from the group consisting of: ~:
a) a radical having the formula
~_~)LN-R4
i~ N~
R5~R6
Q~ :
' : .
.. _ _ .. .. .
..... ~:
5~
.
wherein R4 is a ~r~ember sclccted rlom the group consistin~
oI hydrogell and lower alkyl; and E~ and R6 arc each indepen-
dently selected from thc ~roup consisting o hydrogen, halo
lower allcyl and trifluoron~ethyl;
b) a radical having the Iormula: ~
Y p.
-N/~N N-M
~ ~ ., .
R~R8 ~'
wherein ~7 and R8 are eàch independently selected from the
group consisting of hydrogen, halo, lower alkyl and trifluoro-
methyl; Y is a rnen~ber selected from the group consisting of ~`
O and S; M is a member selected from the group consisting of ~
hydrogen, lower alkyl and lower alkylcarbonyl; and the dotted ~ ..
line indicates that the double bond between the 3 and 4 carbon
atoms of the piperidine nucleus is optional, provided that
when said Y is S then there is a single bond between s~id 3 L
and 4 carbon atoms of the piperidine nucleus and then said ~I ~ .
is hydrogen; . --
- ~,
c) a radical having the rormula~
.
-N~H S(lower alkyl)
R~R
,~' .
'
--4--
... _ _ .. . .
sz
wherein R and ~8are each independently sclected from
the group consisting of hydrogen, halo, lower alkyl and
trifluoromethyl; and
d) a radical having the formula:
r~o~
~Rl ~ .
R
wherein R is selected from the group consisting of -
hydrogen, halo, lower alkyl and trifluoromethyl, and
R is selected from the group consisting of hydrogen and
halo.
As used herein "lower alkyll' may be straight or branch
10 chained and have from 1 to 5 carbon atoms, such as, for example,
methyl, ethyl, propyl, l-methylethyl, butyl, pentyl and the like;
"lower alkenyl" may be a straight or branch chained alkenyl radical
having from 2 to 5 carbon atoms, such as, for example, l-me.thyl-
- ethenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl and the like; and
15 the term "halo" is generic to halogens of atomic weight less than 127, L
i. e., ~luoro, chloro, bromo and iodo. r-
. ~...
. ~
._ .. . .. . ..
5~
Compounds of formula ( I ) which may be rcpresenl;cd by the
formula: _
R 3
B~~(CH2)m~c~l~(c~l2)n- N
R 1\=~\ 2 B~
( I -a )
wherein Rl, R2, R3, m, n and -N JA are as previously defined and
B is as defined for B, but other t~an -NH-C(S)-, are conveniently
prepared by reacting an appropriate reactive ester of formula ( II )
wherein X is an appropriate reactive~ester function derived from the
corresponding alcohol, such as, for example, halo, methanesulfonyl,
4-methylbenzenesulfonyl and the like, wit~ appropriate piperidine
derivative of formula (III) wherein the -N A group is as defined ~
hereinabove. ~J ~;
r..
B~N-(CH2)m~cH-(cHz)n-x + HN~ ~ > ( I-a )
)~X ( III ) .
R R r.
(II) t -
E
The foregoing condensation reaction is preferably carried
out in an appropriate organic solvent, such as, for example, a lower
alkanol, e. g. methanoll ethanol, propanol, butanol and the like
alcohols; an aromatic hydrocarbon, e. g. benzene, methylbenzene,
dimethylbenzene, and the like; a ketone~ e. g. 4-methyl-2-pentanone;
an ether, e.~. 1,4-dio~;ane, 1, l'-oxyl~isetha1le and the like;
N,N-dimethylorman ide; nitrobcnzene; alld the like. The adclition
of an appropriate base, such as, or example, an allcali metal or
earth alkali metal carbonate or hydrogen carbonate, may be utilized
to pick up the acid that is liberated during thc course o the reaction.
A small amount of an appropriate metal iodide, e. g. sodium or
potassium iodide, may be added as a reaction promotor, especially
when the reactive ester of formula (II ) is a chloride.
Somewhat elevated ternperatures are appro~3riate to enhance the
rate o the reaction and preerably the reaction is carried out at
the re1ux temperature of the reaction mixture. In this and following ~_
procedures, the reaction products are separated from the medium
and, if necessary, further purified by the application o methodo
logies known in the art.
Compounds within the scope of formula ( I ) which may be
represented by the formula: t~
HN C N - (CH2 )m~ CH - (CH2 ) - N A i.
t',
R R
(I-b) r
wherein Rl, R2, m, n, R3 and -N A are as previously defined Pf
may also be prepared starting from the corresponding compounds
of ormula ( IV ) 3
P-N~l-(CHz)m-cH-(GH2)n-N
R1 R2
(IV ) i,~
--7-
wllcrein P is an appropriatc protecti~lg group, by the rernoval ~;
o said protccting group according to conventiol~al procedures
as known in the art. ~xan~yles of such protectillg groups arc,
among othcrs, lower alkyloxycarbonyl, 4-methylbenzenesullonyl,
methanesulfonyl and,precrably a subsl:ituted ethenyl group of the
Iormula:
R - CH =C - .
wherein R 11 and R ~ rnay represent diferent
groups but wherein R is preferably lower
alkyl and R 2 is preferably hydrogen, lower
alkyl or phenyl
. .
When the protecting group is lower alkyloxycarbonyl, 4-methyl-
benzenesulfonyl or methanesulfonyl, it may easily be removed
by alkaline hydrolysis, and ~vhen the protecting group is a sub- ~;
stituted ethenyl group it is conveniently eliminated by subjecting ~w -
the appropriate intermediate ( IV ) to acid hydrolysis. r
In carrying out said acid hydrolysis to remove the substituted
ethenyl group from ( IV ) a wide variety of protonic acids may be !-.
employed including mineral acids, such as, for example, hydro-
chloric, hydrobromic, sul~uric, nitric and phosphoric acid, and
organic acids such as, for example, acetic, propanoic 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., methanol, ethanol, 2-propanone and the like.
~'
-8-
_,
, _ ~ _ . .. , ., , ~ . _ . _ . _ . . _ . _ .. . _ _ _ _ _ . ,
Coml~ounds within thc scol~e ol formula ( I ) which may bc
representcd by the ormula: ~
--.
~-(C1~2)m~~H~(CH2)n /
R~R 2
( I - c )
~vherein Rl, X, m, n, R and -N3 are as previously defined
and B is selected from the group consisting of -NH-C(O)-, -NH-C(S)- j~
and -N=CH-, rnay still be prepared by subjecting an approprlate ~
benzenediamine of formula (V ) to rin~g closure ~vith an appropriate r
cyclizing agent, the nature of which,deE~ends on the nature of B in
the desired product.
R3
H2N NH-(CH2) -CH-(CH2)n-N~ ~ closure ~ (I-c ) ' -
R~ \R 2 ) . ~,
The foregoing cyclization reaction may be performed ollowing
art-known procedures of preparing lH-benzimidazoles, 1,3-dihydro-
2H-benzimidazol-2-ones, and 1,3-dihydro-2H-benzimidazol-2-thiones
starting rom l,Z-benzenediamines. Suitable cyclizing agents ~vhich ~
may advantageously be employed to prepare compounds ( I-c ) wherein ~ -
B stands for -NH-C(O)-, include, for example, urea, carbonyl di- ~,
chloride and alkali metal isocyanates, and the cyclisation reaction
z
may bc carried out Iollowing methodologics gellerally known in the art.
For exàmple, when urea is u~ed as the cyclizing agent ~he dcsirecl
compounds are easily obtained by stirring and heating the rcactants
together in the absence of any solvent.
When B in the dcsired compounds ( I-c ) stands or -I~H-C(S)-,
there may be uscd cyclizing agents sucll as, for example, carbon di-
sulfide, thiourea, carbonothioic dichloride, ammonium thiocyanate and
the like, and when B stands for -N=CE~-, there may be used ormic
acid or an appropriate tri(alkyloxy)methane as a cyclizing agent.
In a manner similar to that described hereabove there may
be prepared compounds of the formula: Ç~
3 ~
~-(CHz) -CH-~CHz~) -N~ F
( I - d )
wherein R ,R, R, R, R, m, n, B and Y are as previously
defined, by cyclizing an appropriate benzenediamine of formula ( VI )
with an appropriate cyclizing agent.
I~N -( CH;~ ~ -CH - ( CHz ) -N~(~ y~ a~i" ( I - d )
(VI)
.
- 1 0 - -
'
; .
- ~O~B5i2
In carrying ou~ said cyclizatioll rcac~ion tllcrc may bc usc:d
tlle samc cyclizing a~ents as describcd herel7eIorc lor thc l)rcl~aration
oI com})oullds ( I-c ) starting Iro-n ( V )"norc speciIically Ior the
prep~r~tion of compounds ( I-c ) whercin B stands for respcctively
- NH - C ( O ) - and - NH - C (S ) - .
,,
Still in a similar manner there may be preparcd compounds
of the formula:
Y R _, H Y
HN~ (CH2)m~CH~(CH2)n ~XN~C`NH
R 1~--~R2 R¢/~R8 r
( I- e )
wherein Rl, R, R3, R7, R8, m and n are as previously deIined r,
and the two Y groups are both O or both S, starting from the
corresponding intermediates of formula ( VII ) by cyclizing both ~.
benzenediamine groups in said (VII ) in one reaction step with _:
an appropriate cyclizing agent as described hereinabove for the
preparation of respecti~ely 1, 3-dihydro-1H-benzimidazo1-2-ones
and 1, 3-dihydro-lH-benzimidazol-2-thiones. ,_~
2 ~ H - ( CH z ¦m - C H - ( C H2 )n -N~ c yc li z ati ol~ ~ ( I - e )
R 1 R2 ;,~ '
7 8
(VII ) R R
eh
. _ .
35~
Compounds having the Iormula: ~;
B N - ( C~l 2 ) ~ - C ~ - ( C 1~ 2 )n ~( ,C~ M 1
R I RZ R~R8
( I - )
2 R3 R7 R8 m n and Bl are as previously de
and M is lower alkyl or lower alkylcarbonyl may still be prepared
by respectively N-alkylating or N-acylating the corresponding un-
substituted compound with an appropriate alkylating, respectively r
acylating a,gent following art-known methodologies. The N-alkylation
may e. g. be carried out by the reaction of the unsubstituted compound
with an appropriate reactive ester derived from an appropriate lo~ver ~,
alkanol, e. g., a halo-lower alkane, or a lower alkyl methanesulonate
or 4-methylbenzenesulfonate under similar conditions as described
hereinabove for the preparation of the compound (I-a ) starting from !~
( II ) and ( III ). The acylation may be carried out by reacting the un-
substituted compound with an anhydride or acylhalide derived'~rom
the appropriate lower alkylcarboxylic acid following standard N- ,_~
1~ acylating procedures as known in the art.
- When B in the compounds (I-f) stands for -NH-C(O)-, it is
appropriate to start from an àppropriate compound of formula: ~
R - C EI =C--N N - ( c Hz ) ~ - c H - ( c H z ) -N~ r
Rl R2 R? R8
(IV-a)
--I 2--
5i2
...
which is thcn N-alkylated, resl~ectivcly N-acylated as descril~cd here-
above, whcrcaIter the substituted cthenyl protecting grc)up is elimillate~l
by acid hydrolysis.
l`hose compounds of lormula ( I-f ) wherein Bl stands for
N(L)-C(O)-, said L being a lower allcyl or lower alkylcarbonyl
radical identical Wit]l M, may still be prcpared starting rom an
appropriate compound o formula (I-e ) wherein Y stands for 0, by alkyl-
ating, respectively acylating both lH-benzimidazole groups thcreof in ,~.
one reaction step.
Compounds having the ormula:
>,~
3 H S(lower alkyl) ~:
B~N-(cH2)m-cH-(cH2)n-No(N ~N
R~2 R7 R
(I-g)
may still be prepared starting from a corresponding compound
of formula (I-d) wherein Y stands for S, (I-d-l ), by S-alkylation of
the latter according to standard S-alkylating procedures, e. g., by the
reaction of (I-d-l ) with an appropriate halo-lower alkane or with an
appropriate di-(lower alkyl)sulfate.
The starting materials used in the foregoing preparations may
be obtained following the procedures indicated hereafter I--
'
,
,
-13- _;
'~&~58~,
Reactivc esters oI formula ( II ) which may be represcntcd
by the formula:
R3
(C1~2)m-CH-(C~12),1-X
X~\R 2
( II -a )
wherein Rl, R2, ~3, m, n, B and ~ are as previously deined I -
may be prepared as ollows:
An appropriately substituted 2-chloronitrobenzene of formula
(YIII ) is reacted with an appropriate aminoalkanol ( IX ) by re1uxing
the reactants together in an appropriate reaction-inert organic sol~ent
such as, or example, a lower alkanol, e. g., ethanol, 2-propanol,
butanol and the like, whereupon a ~T2-nitrophenyl)amino7alkanol
of formula (X ) 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 ~-aminophenyl)amino7alkanol of
ormula ( XI ) is then reacted with an appropriate cyclizing agent as
described hereinbefore or the preparation o the compounds ( I-c ).
starting from (V ), and the thus obtained alcohol (XII ) is subsequently
converted into the desired reactive ester ( II-a ) by the application o
r~ethodologies known in the art.
Halides are conveniently prepared by the reaction of ( XI~ i
~ith an appropriate halogenating agent such as, for ex~ample, sulfinyl
chloride, sulfuryl chloride, phosphor pentachloride, phosphor penta-
bromide, phosphoryl chloride and the like. When the reactive ester is
an iodide, it is preerably derived from the corresponding chloride
- ~ _
-14-
~ 5~
or bromidc by the replaccn ent o that halogen with iotline Other
reactive eslers such as methanesulollates and 4-methylbenzene-
sulonates are obtained l)y the reaction oI the alcohol with an appro-
priate sulonyl halidc such as, or e~ample, methanesulionyl chloride
and 4-methyll~enzenesulonyl chloride respectively, ~.-
The foregoing reactions are more clearly illustrated in t1le
iollowing s chematic r epr es entation .
02N Cl R 3
~ _ , I
_ ~ + H2N-(CH2)m~cH-(cH2)n
;..,
Rl R2 (IX)
( VIII )
. . 3
02N NH - (CH2 )m~ CH - ( CH2 )n ~ OH
H2/RaNi >
Rl R2
( X ) , , .
R3
H2N NH-(CH2)m-(~H-(CH2)n-0H
ring closure '
>
R R ,-
(XI) .
~-(CHz) -CH-(CH~) -OH reactive ester lormation (11 a) ~
R2 ' '.:
R ( XII )
'~ .
.~
- 1 5 -
~ 35i~;2
lntcrmecliates o iormula ( Il ) which may bc rcprescl1tcd
by thc Io r mula ~,
R3
(CH2)1n~C~ (c~l2)n
R 1 R2
( II-b )
wherein Rl, R2, R3, m, n and X are as previously defined and B
is selecl:ed from the group consisting of -S-C(O)-,-O-C(O)-, -N=N-,
-N=CH-, and -N(Ll)-C(O)- wherein Ll is lower alkyl, lower
alkenyl, or lower alkylcarbonyl,may also conveniently be prepared by
the introduction of the reactive ester side chain into a starting material
of the formula
B~ H
Rl R
( XIII ) -
- following procedures known in the art. For example, one may first
introduce a hydroxyalkyl chain by N-alkylating ( XIII ) ~vith an appropriate
haloalkanol of forn ula ( XIV ) following common N-alkylating procedures
to obtain an alcohol of formula (XV ), the hydroxyl group of which is
subsequently converted into a reactive ester group according to ~;~
conventional procedures as previously described. ~ ~ .
In place of the haloallcanol ( XIV ) there may also be used a tetrahydro-2H- r
pyran-2-yl ether derivative thereof, in which case the corresponding ether -~
.
- i 6- . ~
.
, ... . . .
5i2
derivative of (XV) is obtained, the ether function of which is
split open by acid hydrolysis, e.g., by stirring and heating
the ether compound in diluted hydrochloric acid.
When the reactive ester (II-b) is a halide, (II-b-l),
it may alternatively be prepared by the reaction of (XIII)
with an equivalent of an appropriate dihaloalkane (XVI), in
the presence of an appropriate strong base such as, for example,
sodium methanolate, or following a Mackosza procedure using
aqueous alkali and a quaternary ammonium catalyst, e.g., N,N,N-
triethylbenzenemethanaminium chloride, yielding the desired
intermediate (II-b-l).
The foregoing procedure may be illustrated as follows:
R3
(XIII) + halo-(cH2)m-cH-(cH2)n-oH N-alkylation
(XIV)
~ I reactive es-ter for~ation
B ~ -(CH2)m-CH-(CH2)n-OH ~ (II-b)
~)
~\ .
Rl R2 (XV)
R3
(XIII) + halo-(CH2)m-CH-(CH2)n~hal base
R3
~- (CH2 ) m-CH- (CH2 ) n-halo
1\~\
Rl R2 (II-b-l)
- 17 -
Inl:cr1ncdiatcs oL ~:he formula: ~
R 3 r_
I-~N N-(C112)~n-CH-(C}-~2)n-X
~ . ;
y--~( 2 6~.
R1 R
(II-c )
wherein R, R, R3, m, n and X are as previously defined may
still be prepared by introducing the reactive ester side chain into
a starting material of formula ( XVII )
I r
P-N~C~H
/~ 2 ,
R R k:
( XVII )
.
wherein P is an appropriate protecting group as previously defined,
and ~hereafter eliminating the protecting group of the thus obtained ~~ .
(XIX ) according to art-known procedures as described hereinabove.
The introduction of the reactive ester side chain may be performed
foilowing similar procedures to those described hereabove for the ~.-
introduction of said chain into starting materials of formula (XIII ).
More particularly there may be first introduced a hydroxyalkyl chain,
whereafter the hydro~;yl group o the thus obtained intermediate ( XVIII )
is converted into a reactive ester group to obtain (XIX ), or, when
the reactive ester is a halide, (XIX-a ) said halide may be obtained
directly by the reaction o (XVII ) with an appropriate dihaloalkane.
.. k
.~ .
-18-
_ _ _ . . .
.
~ 51~5Z
When the protectin~ P i5 one sul)jcct to alkali~le hydrolysis, e. g., alower alkyloxycarl~onyl, methanesulIonyl or 4-mctllyll~cnzencsul~otlyl
group, thc N-alkylatioll reaction to introducc respcctively thc hydro~:y-
alkyl or haloalkyl chain should l~e carried out under non-hydrolytic
conditions, using or e~amplc a1~ appropriate metal l~ase such as,
for example, sodium hydride or sodium methanolate in an appropriate 'E~
aprotic organic solvent such as, Ior example, N,N-dimethylformarnide, ~:
N, N-dimethylacetamide or he~amethylphosphoric triamide.
The foregoing reactions are more clearly illustrated in the ~;
following schematic representation. 1 IR
( XVII ) + N-alkylation p N~C N-(CH2)m-CH-(C 2~n
.` ~) ,
~ ' ' ',
+(XVI) Rl R2 ~ ~1
\ / ( XVIII ~ :
reactive ester ~.
formation
P N~ (C ~)m ( ~)n p_l~C N ) -CH-(CH~) -X
¦ ( XIX-a ) ( XIX ) t~
elimination of P .
elimination of P ~-
1l R 3 ~ / s~
H~ ~-(cH2)m-cH-(cH2)n-halo ( II-c ) ~,
)~2
R R
(Il-c-l )
~;:
- 1 9~
' .
. ~
~ 5Z
Intcrmcdiatcs having the Iorlllula - ~
R R3
L -N ,~-CH2-CII-C~I2-X
~,
R 2 '
( II-d ~ _
wherein R , R, R and X are as previously de~ined and L2 is L,'
lower alkyl or lower alkenyl, said lower alkenyl having its unsaturation
at the ~, ~or ~-position, may still be prepared as follows.
An appropriate intermediate of formula ( II - c ), wher ein
m and n are each 1, (II-c-2 ), is treated with sodium metal in : -
absolute ethanol whereby a cyclic ether of formula ( XX ) is formed 7~p
The latter is subsequently reacted with an appropriate reactive ester
L X, ( XXI ), wherein L and X are as previously defined, e. g., by
reflu~cing the reactants together in a:n appropriate organic solvent F~
such as, for example, 2-propanone, whereby the desired intermediate
(II-d ) is ob~ained L
O R3
HN C ~-CH2-CH-CH2X Nà ~ R2~ N~LR3
~ absolute ethanol ~ .
~ . ( XX ) '~ '
R R
(Il-c-2) . ~",
. . I ' .
L X ~ ( II-d )
( XXI )
~,
-20 -
~,
_ . . .
The compounds o~ Iormula ( lV ), uscd as intcrmediates in
thc prcparation o thc compounds ( I-b ), may gcnerally bc obtai1led
by a condcnsation rcaction oI an inter1nediate ol ormula (XIX )
with an appropriate intermediate oI Lormula ( III ) undcr similar
conditions to tllose described hereinabove for the preparation o~ the
compounds ( I-a ) starting rom ( II ) and ( III ). ~
(XIX ) + ( III ) > (IV ) - _
Those intermediates o formula ( IV ) wherein -N A
has the formula V
~'
H X !-
)~N NH
~' ' ;.'
R~XR8 ~-
and which are indicated as ( IV-b ) may still be prepared by the
condensation of an appropriate reactive ester of formula (XIX ) ~`~
with an appropriate N-(2-nitrophenyl)-4-piperidinamine of
ormula ( XXII ), followed by the reduction of the nitro group of the ._
thus obtained (XXIII ).according to standard nitro-to-amine reduction
procedures, e g., by the reaction of the nitro compound with nascent
hydrogen or by catalytic hydrogenation in the presence o an appropriate
catalyst such as, for example, Raney-r~ickel, and cyclization o the
resulting benzenediamine ( X-XIV ) with an appropriate cyclizing agent
as described hereinabove.
The foregoing reactions are illustrated in the ollowing ~
schematic representation r
:.
( XIX ) + HN X
~J NH NO2
, )(~ .
f7~ 7 ~ 8
( XX II )
--2 1 --
p~ (C~lz)m~CH~(Cllz)
( XXIII )
O R3 ^
nitro-to-am~ P-N N-(CI-J2)m-~;~J-(cH2)n `~H
reduction ~ R ~ l`lH NHz
( XXIV)
~ cyclization
( IV -b )
The starting materials of formula ~XXII ) herein may be - -
prepared ollowing the procedures outlined in U. S. Pat. No. 3, 910, 930.
The intermediates of ormula ( V ) are obtained by the
condensation of an appropriate reactive ester of formula (XXV ) with
an appropriate piperidine derivative of formula ( III ), ollowed by the ~-.
; reduction of the nitro group of the thus obtained intermediate ( XXVI ) h.`~
to an amino group according to standard nitro-to-amine reduction
procedures.
-22 -
51~Z
-
1~3
OzN Nl~-(C1~2)m~~;}]~(CH2)n~X + ( 111 ) >
Rl R
( XXV )
lR3
02N NH-(C~J2)m-CH-(CH2)n-N~ nitro-to-amine ~ (V )
r e du ction
~( 2 r
R - R
( XXVI )
~.
The reactive esters o formula (XXV ), used as starting materials
herein are easily prepared starting from an alcohol of formula ( X )
by the conversion of the hydroxyl function thereof into a reactive ester
group ollowing standard procedures as previously described herein. p~
,
The intermediates of formula ( VI ) may generally be
prepared by the condensation of an appropriate reactive ester of ~.
formula ( II ) with an appropriate N-(2-nitrophenyl) -4-piperidin-
amine of formula (XXII) and subsequent reduction of the nitro
-- group of the thus obtained ( XXVII ) to an amine group following
standard nitro-to-amine reduction procedures as previously
de s cribed.
It is to be noted that when the nitro-to-amine reduction is accom- -
plished by catalytic hydrogenation using palladium-on-charcoal
catalyst there may occur dehalogenation in compounds wherein 1~;
aromatic halogen substituents are present. ~
; .
. ~:
p~
~1~8~
(Il) + (XXII) ~ ~CI-Iz) ~ l-(C~Iz) -N~
'
( XXV II )
nitro-to-amine ( VI )
.
r edu ction
~ .
The intern ediates of formula (VII ) may sinlilarly be
prepared by the condensation of a reactive ester of formula (XXV )
with a piperidine derivative of formula (XXII ) followed by the reduc- ,
tion of both nitro groups in the thus obtained ( XXVIII ) according to ~0
5 standard procedures as previously indicated.
(XXV) + (XXII) _3. OzN~NH-(CHz) -CH-(CHz) -N~\i~
R 2 ,~
( XXVIII ) R R
F~
~.
nitro-to-amine L_
- ~ (VII) 5~ .
r eduction ~: ~
, ~
_Z4--
_
Starting nlaterials of formula ( III ), represented l~y the
~,
Ior mul~ s:
~- N 1 4 b ) H l~
R~R6 ~7 \ 8
( III-a ) ( III-b )
- /OH i~
3 r
9~' 1 0
( III - c )
and methods of preparing the same may respectively be found in E~
the ollowing relerences:
- ~.
5 a) U.S.Pat. No. 3,238,216; ,~
b) IJ, S. Pat. No. 3, 161, 645;
Belg. Pat. No. 830, 403;
c) U.S.Pat. No. 3,518,276; and
U. S. Pat. No. 3, 575, 990. ~-
- ~
10Starting materials of ormula (III) which are represented
by the formulas:
~\ H S /--\ H S-(loweralkyl)
HN ~ 11 and HN ~( I
`N~C`~ N'C~N
l~R 8 R~R 8
(III-d) (III-e)
,
.
-25 -
5~
may gen.crally be pre~ared st:art:ing frorn an appropriate N-(2-amino-
phenyl)-4-piperidinE1mine o formula~
(lower alkyl)-O-C-N~(H
N H 2 j.
R R
( XXIX )
The starting materials (III-d ) are conveniently prepared
by the cyclization o ( XXIX ) with an appropriate cyclizing agen~ r
e. g., carbon disulfide and subsequent remo~al of the lower alkyl-
oxycarbonyl group of the thus obtained ( XXX ) by alkaline hydrolysis
Thc starting materials ( III-e ) can be prepared by S- ,,,
- alkylating (XXX) as described hereinabove followed by eliminatio~
of the lower alkyloxycarbonyl group of the resulting (XXXI ).
The N-(2-aminophenyl)-4-piperidinamines of formula (XXI~ ),
a number of which are known compounds, may be prepared. ollowing
the procedures outlined in U;S. Pat. No. 3, 910, 930 and Belg. Pat, ~
No. 830, 403, ~;
The oregoing procedures are illustrated in the following
schematic representation. ` ..
(lower alkyl)-O-C-N~(
N H 2
~
7 8 5
R R
( XXIX )
_26 -
~35~Z
( XXIX )
~ cycli;~,ation
( low er al~yl) - O - ~ -N~ ~ ~ ( Ill -d )
XXX )
.,~
S-alkylation ~,
~ /
H S-(lower alkyl) OH
(lower alkyl)-O-C-N~(N~C~ (III-e )
Ft
R7 R8 r
.
( XXXI ) w
- The ultimate s$arting materials in all of the oregoing pre .
parations are generally known or their preparation may be performed
following art-known procedures o~ preparing similar compounds. E
For example, the preerred starting materials of ormula
( XVII ) wherein P is an appropriately substituted ethenyl group,
(~CVII-a), an important number oI which are known compounds, may ~ .
be prepared following the procedures outlined in J. Chem. ~oc., 1960,
p. 308 and p. 314.
.
'
- 2 7 -
.
~5~
More p,~rticu]arly SUCII compounds arc convcniellt1y prc~ared l~y thc
rcactio1l oL a1l appropriatc ester, o~ tlle formula ( XXXJI ) wherein R ,.
and r~12 have thc previously indicat~-,d mcani11g, with an appropriate
benzc1lediaminc of Iormula (XX~I]I ), Said reaction is preIerably
carried out by stirring and rc~luxing thc reacta1lts together in an
appropriate rcaction-inert orga1lic solvcnt with azeotropic water
removal, Suitable reaction-inert or~anic solvents ~or this purpose ~,
include, or example, aromatic hydrocarbons SUCII as benzene, methyl-
ben7ene, dimctllylbenzene and the like,
O ~,
R12-CH-C-O-(lower alkyl) ~H2N\ /N 2 >
C--O
Rl R i:
( XXXII ) ( XXXIII ) r
- .
0~ ,~
~ ',.
R R
( XVII-a ) ~ _
- 2 8 -
1 ~.
,~
5~
Thc inl;ermcdiatcs of formulas (V ), (VI ) and (~II ) are dcemcd
to be novcl and, as uselul intermcdiates in the prepar;ltion of l.hc dcsircd
compounds oI ormula ( I ), thcy constit-lte an additional fcaturc oL this
invcntion .
The compounds of this invention may be converted to their
therapeutically useful acid addition salts by treatment ~vith an
appropriate acid, such as, for example, an inorganic acid, such as r
hydrohalic acid, e. g., hydrochloric, hydrobromic, and the like; and
suluric acid, nitric acid, phosphoric acid and the like; or an organic
acid, such as, for example, acetic, propanoic, hydroxyacetic, 2-
hydroxypropanoic, 2-oxopropanoic, propanedioic, butanedioic, (Z)-2- h
butenedioic, (E)-2-butenedioic, 2-hydroxybutanedioic, 2, 3-dihydroxy- ~
butanedioic, 2-hydroxy-1, 2, 3-propanetricarboxylic, benzoic, 3-phenyl- ~q
2-propenoic, ~;-hydroxybenzeneacetic, methanesulfonic, ethanesulonic,
benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfamic,
2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids.
Conversely the salt form -can be converted by treatment with alkali ~,
into the free base form.
~'
'
The compounds o formula ( I ) and the therapeutically --
active acid addition salts thereo have been found to possess strong
- antiemetic activity as is evidenced by their ability to block apo-
morphine-induced vomiting in dogs. The nlethod used is described
previously by P. A. J. Janssen and C. J. E. Niemegeers in:
Aræneim. -Forsch. (Drug Res.), 9, 765-767 (1959).
~.
,
'
/
llDt35B52
,
The compounds listcd below were administered sub~
cutaneously to beagle dogs at different doses and the animals were
challenged 1 hour thereafter with a standard dose of 0. 31 mg/kg
(subcutaneous) of apomorphine.
The tables below give the ED50 values of a number of P:
the compounds under consideration. As used herein the ED50
value represents the dose which protects 50% of the animals
from emesis.
,
It is understood that the compounds shown in the 9",
tables are not listed for the purpose of limiting the invention
thereto, but only to exemplify the outstanding antiemetic -~
properties of all the compounds within the scope of formula (I ).
....
.,~.
- ' _
'
.
-30-
.
.
. .
Sl3~2
TABLE I
O O
~ C ~ ~ -R
L-N N-CH2-CH2-CH2-N ~ ~
R R
R R R
H H H H 0.03
H 5-Cl H H 0.05
H 5-CH3 H H 0.06
CH3 H H H 0.08
CH2=CH-CH2 H H H 0.25
H H H 4-F 0.04
H 5-Cl H 4-F 0.015
H H H 3-CF3 0.025
_ H CH3 H 0.015
- 31 -
~851~;Z
TABLE I I
O O
, C ~ IR3 ~ C ~
L-N N-CH2-CH-CH2-N3--r~ /NH
X~ \ ~/
\
Rl R \ 7
R
_ Salt and ED50
L Rl R2 R3N~ R7Solvate formmg/kg s.c.
H I H 11 N~> H _ O. 02
H 5-Cl H H ll H _ 0.10 :
H 5-CH3 6-CH3 H .. H CH2-CHOH-CH3 0. 45 ~
H H H ~H3ll 5~1 _ 0. 06 ~ :
H H H H ll 5-Cl _ 0 . 01
H 5-Cl H H ll 5-Cl _ 0 .12 :
CH3 H H H .l 5-Cl _ 0 .16
CH2=CH-CH2 H H H ll 5-Cl _ 0 .12
H H H H N~ H _ 0.04
H 5-F H H N~7 5-Cl HCl H20O . 004
H 5~H3 H H ll S--Cl HCl H2O0.12
C ~CH3 ) =CH2 H H H ll 5-Cl _ 0 . 2 0
5-CEI3 H H _ H HCl H20O . 20
. ~ ~
, ~:
: . . .
. . .. ...
~85~5~
TABLE I I I
Il OH
L--N l-C}l2--C~2--C~12-N
~;
L¦ R R ng~ I:r 3
H 4-Cl H 0. 06
CH2=CH-CE[2 4-Cl H 0. 50
4-Cl3-C~3 015 ~'
-- 33 --
'IA~3 I r; IV
1~ iZ
_ Co~nl)oul~d ~ 50 ~ /J<~ ~. c~
N~N-(C~2)3-N~ 0,25
5~3N ( H2)3 N~N"'NH
~ N - ( C 2 ) 3 ~ ~NI I 0 . D 3
( Z)3 ~N~H 0. DD4 !~
~ (~ 2 3 ~r~H 0. 06
HN~ -(CH2)3 3(N~H D, D25
Z)3 ~XN N~I D D04
. - - - - 3 ~
.
~ In view o their uscful alltieme(:ic a.ctivily, the sul~ject
compounds may be formulated into various pharmaceutical Iorms
for administration purposcs. To prepare the pharmaceutical com-
positions of this invention, an ecctive antiemctic amount ol the
particular compound, in base or acid-addition salt form, as the
active ingredient is combilled in intimate admixture with a pharma- E~
ceutically acceptable carrier, which carrier may take a wide variety G~-
of orms depending on the form of preparation desired or administration.
These pharmaceutical compositions are desirable in unitary dosage
Iorm suitable, preferably, for administration orally, rectally or by
parenteral injection. For example, in preparing the compositions
in oral dosage orm, any of the usual pharmaceutical media may be ~i
employed, such as, or example, water, glycols, oils, alcohols and
the like in the case of oral liquid preparations such as suspensions,
syrups, elixirs and solutions; or solid carriers such as starches,
sugars, kaolin, lubricants, binders, disintegrating 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 c
advantageous oral dosage unit form, in which case solid pharma-
ceutical carriers are obviously employed. For parenteral compositions, -~
the carrier will usually comprise sterile ~vater, at least in large part,
though other ingredients, for example, may be prepared in which the
carrier colnprises saline solution, glucose solution or a mixture of saline
- and glucose solution. Injectable suspensions may also be prepared in ~vhich, -
case appropriate liquid carriers, suspending agents and the like may
be employed. Acid addition salts of ( I ), due to their increased ~vater
solubility over the corresponding base form, are obviously more .~
suitable in the preparation of aqueous compositions. . a '~' .
~',
It is especially advantageous to ormulate the aforementioned r
pharmaceutical compositions.in dosage unit form for ease of administra-
tion and uniormity oI dosage. Dosage unit form as used in the specifi-
. cation and claims herein refers to physically discrete units suitable as
,
. . _ . . .
~D~3;5~2
unitary dosages, each unit containing a predetermincd quarltity of
active ingredicnt calculated to produce the dcsircd therapeutic ellcct _.
in association with the required pllarrnaccutical carrier ~:xalnples
of such dosage unit forms are tablets (illcluding scored or coated
tablets), capsules, pills, powc1er pacl~ets, wafers, injectable
solutions or s~lspensions, teaspoonIuls, tablespoonfuls and thc lil;c,
and segregated multiples thereof. ~,;
The amolmt o active ingredient per-dosage unit will be
from about 0. 25 mg to about 100 lng and, preLerably from about 1
to about 50 mg.
The ollowing Iormulations exemplify typical antiemetic r
pharmaccutical compositions in dosage w~it Iorm suitable for systemic
adlninistration to animal and human subjects in accordance with
the instant in~ention.
Oral drops: The ollowing formulation provides 50 liters of an
oral-drop solution colnprising 10 milligrams of 5-chloro-1-
3-(2, 3-dihydro-2-oxo-lH-benzimidazol-1 -yl)propylJ-4_
piperidinyl~-1,3-dihydro-2H-benzimidazol-2-one as the active
ingredient (A I. ) per milliliter.
A.I. --~ --------- grams
2-hydroxypropanoic acid ~------ 0. 5 liter
Sodium saccharin ------------- 1750 grams tE
Cocoa flavor _-____________ ___ 2. 5 liters ~
Purified water _ ___________-__ 2. 5 liters _`
Polyethylene glycol q. s. ad_____ 50 liters ~.
- 3 6 - ~
' .
.
z
, Thc A, I, is dissolvccl in the Z-~lydroxyprop;l1loic acid and
I, 5 litcrs of the polycthylc1-c glycol at 60-80C, Artcr cooling to
30-40C thcre are addcd 35 liters of po]yethyle1lc glycol and the
mi~;ture is stirrcd well. Thcn therc is added a solution ol the
sodium saccharin in 2, 5 liters oI purified ~vater and while stirring
there are added the cocoa Ilavoi and polyethylcne glycol q. s. ad
volume. The resulting solution is lillcd into suitable containers, 5
Injectable solution. The following formulation provides 20 liters of
a parenteral solution comprising 2 milligrams o 5-chloro~
~-(2, 3-dihydro-2-oxo-lH-benzimidazol-l-yl)propyl7-4-piperidinyl~l - P~
1, 3-dihydro-2H-benzimidazol-2-one as the active ingredient per r
milliliter, ,
A,I.____---_--------------------- 40 grams
2, 3-dihydroxybutanedioic acid------ 20 grams
methyl 4-hydroxybenzoate--------- 36 grams ~ ~
propyl 4-hydroxybenzoate --------- 4 grams
water for injection q. s. ad 20 liters
,, ~
The methyl and propyl 4-hydroxybenzoates are dissolved in
about 10 liters of boiling water for injection. After cooling to about
- 20 50C there are added while stirring the 2, 3-dihydroxybutanedioic
acid andthereafterthe A.I.. The solution is cooled to room tcmperature ~.'
and supplemented with water or injection q. s. ad volume. The ¦~
solution is sterilized by iltration ( U . S. P. XVII p. 81 1 ) and filled
in sterile containers. L~
r.~
-37-
i ~.
_. ~
Oral solution: Thc lollowing ormulation providcs 20 lil:ers of an
oral solution comprising 5 milligrams oL 5-c~lloro-1- il -~-(2, 3-
dihydro-2-oxo-111-bcnzirnicla~ol-1-yl)propyl7~ piperldinyl ~-
I, 3-dihydro-2I~-ben~imidazol-2-one as the active ingredicnt per
teaspoonlul (5 milliliters)
A I.-~ --------- 20 grams ~'
2, 3 - dihydroxybutanedioic acid - - - - - - -- 1 0 grams
Sodium saccharin______ ___________ 40 grams
1, 2, 3 -propanetriol ____ _____-----__ 12 liters
Sorbitol 70% solution _______________ 3 liters
Methyl 4-hydroxybenzoate ---------- 9 grams
Propyl 4-hydroxybenzoate --_-------- 1 gram
Raspberry essence ______ _______ __ 2 milliliters
Gooseberry essence _-___----------- 2 milliliters
Purified water q. s. ad 20 liters
r~
The methyl and propyl 4-hydroxybenzoates are dissolved
in 4 liters of boiling purified water. In 3 liters o this solution are
dissolved first the 2, 3-dihydro~ybutanedioic acid and thereafter
the A. I. . The latter solution is combined with the remaining part
Z0 of the former solution and the 1, 2, 3-propanetriol and the sorbitol -~solution are added thereto. The sodium saccharin is dissolved
- in 0. 5 liters of water and the raspberry and gooseberry essences ',
are added. The latter solution is combined with the former, water 1~
is added q. s. ad volume and the resulting solutioil is filled in ~ -
suitable containers.
. ~.
Film-coated tablets: 10,000 Compressed tablets, each containing
as the active ingredient 10 milligrams o 5-chloro-1- ~ 3-(Z, 3-
dihydro-2 -oxo- 1 H-benzimidazol- 1 -yl)propyl7-~ -piperidinyl ~ -1, 3-
dihydro-21~-benzimidazol-2-one, are prepared from the ollo~ving
ormulation:
~- 3 8 -
, ' ' ' ' ' ~
Tal~le~: core: ~:
A, I. ~ - grams
- Lactose ---------------------------- 570 grams
Starch ---------------------------- 200 grams
Polyvinylpyrrolidone (~Collidon K 90) - 10 grarns
Microcrystallinc cellulose (Avicel)---- 100 grams j~
Sodium dodecyl sulate--------------- 5 grams
Hydrogenated vegetable oil (Sterotex)-- 15 grams
Coating: k
Methyl cellulose (Methocel 60HG)------ 10 grams
- Ethyl cellulose (Ethocel 22 `cps)-------- 5 grams
I, 2, 3-Propanetriol --------- ~ --- 2. 5 milliiiters
Polyethylene glycol 6000 -------------- 10 grams
Concentrated colour suspension -------- 30 millili~ers
(Opaspray K-l 2109) ~-
Polyvinylpyrrolidone (Povidone)------ 5 grams
Magnesium octadecanoate --- --------- 2. 5 grams
'
PrepaTation of tablet core:
A mixture of the A. I., the lactose and the starch is mix~d ~.
well and~erea~ter humidified.with a solution o the sodium dodecyl
sulfate and the polyvinylpyrrolidone in about 200 milliliters of water.
The wet powder miYture is sieved, dried and sieved again Then
there is added the microcrystalline cellulose and the hydrogenated r
vegetable oil. The whole is mixed well and compressed into tablets.
~.'.
-39- ~.
.
Co~ti~
Y
il
To a solution o~ the mcthyl cellulose in 75 millilitcrs of
denaturated ethanol tllerc is addcd a solution of thc ethyl cellulose
in 150 millilitcrs of dichloromethane Thcn there are added 75
milliliters of dichloromethane and the I, 2, 3-propanetriol. The
polyethylene glycol is molten and dissolved in 75 millilitcrs of
dichloromethanc. The latter solution is added to the ormer and
then there are added the magnesium octa~ecanoate, the polyvinyl-
pyrrolidone and the concentrated colour suspension and the whole
is homogenised.
The tablet cores are coated with the thus obtained mixture
in a coating apparatus.
Suppositories: Hundred suppositories each containing 30 milliarams
of 5-chloro-1- ~ -(2, 3-dihydro-2-oxo-lH-benzimidazol-l -yl)-
propyl7-4-piperidinyl } -l, 3 -dihydro-2H-benzimidazol-2 -one as the
active ingredient are prepared from the following formulations:
q - .
.
A . I . - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - 3 grams
2, 3-Dihydroxybutanedioic acid ------- 3 grams
- Polyethylene glycol 400------------- 25 milliliters
Surfactant (Span) ---_-__--------_ l 2 grams
Triglycerides (Witepsol 555 ) q. s. ad 300 grarns.
The A. I. is dissolved in a solutioll o the 2, 3-dihydroxy-
butanedioic acid in the polyethylene glycol 400. The sur~actant and
the triglycerides are molten together. The latter mixture is mixed
- well with the former solution. The thus obtained mixture is poured
.
,' ~.
0 -
'~ ~
SI~5Z
int:o mould6 at a ten~perature of 37-38C lo form the suppositories.
In view oI the antiemetic activity of the subject compounds,
it is evident that the present invention provides a rnethod of inhibiting
emesis in warm-blooded animals by the systemic administration of
an effective antiemetic amount of a compound of formula ( I ) and the
pharmaceutically acceptable acid addition salts thereof in admis~ture
with a pharmaceutical carrier.
The following e}:amples are intended to illustrate but
not to limit the scope of the present invention. Unless other~vise
stated all parts therein are by weight.
-41 -
~,
~, ,
~85~i2
Eæa mpl e I _
A mixture c~f 100 parts of 1-chloro-2-nitro-4-(trifluoro-
methyl)benzene, 90 parts of 3-amino-1-propanol and 200 parts of
butanol i5 stirred and heated till reflux. Stirring at re1ux is
continued overnight. The reaction mixt~re is cooled and evaporated.
Water is added to the residue and the whole is acidified with a
hydrochloric acid solution. The product is e~txacted with ~ethyl-
benzene. The extract is dried, filtered and evaporated. The solid
~esidue is crystallized from petroleumether. The product is filtered
off aDd dried, yielding l~Ll parts (100 %) of 3- ~-nitro-4-(trifluoro-
methyl)phenyl7amino ~-l-propanol.
~: .
.. _, .. . . . .. ~ .. .. . . .. , . . . ., . . . .. . . _ . .. , .. . . .. , .. - ..... ... . .. _ _ .
Ex~e II :
Following the pr~ edure of E~ample I and usmg equivalent amounts
of the appropriate starting materials there a.re prepared: -
_, .
3-~4-methyl-2-~itrophenyl~amino7-1-propanol as a resldue;
3-~4,5-dichloro-2-~itrophenyl)amino7-l-prQpanol; mp. 97C; and
3-~2-chloro-6-nitrophenyl~amino7-1-propanol as a residue.
. ' - ' ~ . ' ' , ' " ' ~' ~
42
,
'
,
.,
... ~ .
:: . ~ . ;, .
~135i852
Example III
A mixture of 70 parts o~ 3-~4-methyl-2-nitrophenyl~-
amino7-1-propanol and 400 parts of methanol ;s hydrogenated
at normal pressure and at room temperature with 10 parts of
palladium-on-charcoal catalyst 10%. After the calculated
amount of hydrogen is taken up, the catalyst is filtered off and the
filtrate is evaporated, yielding 54 parts ~91 %) of 3-~2-amino-4- .
methylphenyl?amir o~- 1 -propanol as a residue.
.
~.
Example IV
,'' .'
A mixture of 141 parts of 3- ~ nitro-4-(trifluoromethyl)-
pheny~7arnino}-1-propanol and 1200 parts of methanol is hydrogenated :
at normal pressure and at room temperature with 15 parts of Raney- ~: -
nickel catalyst. After t~ie calculated amount of hydrogen ;s taken up, ;~the catalyst is filtered o~f and the filtrate is evaporated. The residue .:is crys.tallized from 2, 2'-oxybispropane, yielding 110 parts (lG07~)
of 3~ amino-4-(trifluoromethyl)phenyl7amino.}-1-propanol.
... . . .. . . , . , ,,, ,,, ~
-
''
43
"
-, , , :,
~s~sæ
Example V
. '
Following the procedure of Example IV and using equi-
~ralent amounts of the appropriate starting materials there are pre-
pared:
3~ an~ o-4, 5-dichlorophenyl~amino7-1-propanol hydrochloride; :;
mp ~ 185C;
3~ ami~o-6-chlorophenyl)amino~ propanol as a residue; arld
.
3 ~0arnino-4 chlorophenyl)aminoJ l propanol as an oily residue.
Example VI r
To a stirred and cooled solution of 54 parts of 3-~2-amino-
4-nlet~lphenyl)amino7-1-propa~ol in 30 parts of hydrochloric acid ;
colution 10% and 200 parts of water is adde~ dropwise a solution
of 28 parts o potas -ium cyanate i~50 parts of water at a ternperature
below 10C;. Vpon completion, stirring is continued first ~r 1 hour :
at room temperature and ~urther for 24 hours at reflux temperature.
A~ter cooling to room temperature, the product is extracted with tri- -
chloromethane. The extract is washed with a hydrochloric acid soiution
5%, dried, filtered and evaporated. The re.sidue is crystallized rom
~-methyl-2-pentanone, yielding 19,5 parts (31%) of 1,3-dihydro-
1 -(3-hydroxypropyl)-~-metl~y1-2H-benzimidazol-2-one; mp. 114. 1 C.
~ .
',
44 . - ~:
,
.: .
~C98~ 352
Example VII
'
Following the procedure of Example Vl and using equi-
valent amounts o~ the appropriate starting ~naterials there are
prepared:
1, 3 -dihydro -1 -(3 -hydroxypropyl)-5 -(tri~luoromethyl) -2H-benz - ;
imidazol 2-one;
,
5, 6-dichloro-1, 3-dihydro-1-(3-hydroxypropyl)-2H-benz-
i~nidazol-Z-one; mp. 1740 7C;
''~
- 4-chloro-1, 3-dihydro-3-(3-hydroxypropyl)-2H-benzimidazol-2-one; i~
a2~d
,~
5-chlo~o-1, 3-dihydro 1 -(3-hydroxypropyl) -ZH-benzimidazol-2-
one; mp. 148.8C.
,' .
ample VIII
To a stirred solution of 18.5 parts of 1,3-dihydro-1-
(3-hydroxypropyl)-5-methyl-2H-benzimidazol-2-one in 325
parts of dichloromethane are added 11.9 parts o~N,N-diethyl-
ethanamine. Then there are added dropwise (610wly) 1l. 5 parts
of methanesulfonyl chloride. Upon completion, stirring ;s conti~
~ued for 1 hour at reflux temperature. After cooling, the reactioll
mixt~lre is washed with water, dried, filtered and evaporated. The
sol;d residue is crystalllized ~om 4-methyl-2-pentanone, yielding
15 parts (58%3 o~ 1,3-dihydro-1-(3-hydroxypropyl)-5-methyl-2H-
benzimidazol-2-one methanesulfonate; mp. 125C.
.. ..... , .',
~.
Example IX ~08S~352
Following the procedure of Example VIII and using equi-
valent amounts of the appropriate starting materials ,here are
prepared: -
3 -(5, 6-dichloro-~, 3-dihydro-2-oxo-lH-benzinlidazol-l -yl)-
propyl methanesulfonate as an oily residue;
. . .
3 -( 7-chloro-2, 3 -dihydro -2 -oxo - l H-benzimidazol- l -yl)propyl
methanesulfonate; and - .?
.
3-(5-chloro-2, 3-dihydro-2 oxo-lH-be~zimidazol-l-yl)propyl
methan e s ul~onat e; mp . ~ l 40 C .
'
Example X
A mixture of 30 parts of lH-benzimidazol, ~9 parts of 2-
(4-chlorobutoxy~tetrahydro-2H-pyran, 21 parts o potassium hydroxide
and i~OO parts of ethanol is stir~ed and refl~Lxed overnight. __
The reaction m~xture i5 cooled to roorIl tcn~perature, iltered and the ~
filtrate is evaporated. The residu~ is stirred in water and acidificd
with a diluted hydrochloric acid solution. The whole is stirred and
heated for 30 minutes in a water-bath. ~fter cooling to ~oom tempera-
ture, the product is extracted with methylbenzene The aqucous phase
is separated and alkalized with ammonium hydroxide. The product is
extracted with dichloromethane. The extract is dried, iltered and
e~raporated, yiclding 50 parts of lH-benzimidazole-l-b~ltanol as
an oily residue.
46
- ~,
: - ~ ' .,: `
,:
5~5%
Example XI
.. . . ..................................... . .
To a stirred mixture of 23 parts of 1, 3-dihydro-l-(3-
hydrox~propyl)-5-(trinuoromethyl)-2H-benzimidazol-2-one in
150 parts of trichloromethane are added drop~vise 32 parts of
sulfinyl chloride. Upon completion, the whole i8 heated to reflux
and stirring is contimled for 1 hour at reflux temperature. After
cooling, the reaction nli~cture is evaporated and the residue is
crystallized from 2, 2'-oxybispropane, yielding 14 parts (56%)
of l-(3-chloropropyl)-1,3-dihydro-5-~trifluoromethyl)-2H-
benzimidazol-2-one.
... .. ... . . .. .... .. .. .
.. , .- --- ~
.: r
Example xn
.
Following the procedure of Example XI and using
therein an equivalent amount of an appropriate hydroxy corn-
pound as a starting material the following chlorides are
prepared~
~,,
5 -ChlOTO~ 3-clllo~oprc~py~ 3-dihydro-2H-benzimidazol-2-one;
~ -
6-chloro-1 -(3 -chloropropyl)- 17 3 -dihydro-2H benzirnidazoi-
2-one; 3np 122C; and
1-(4-chlorobutyl)-lH-benzlmidazole as an oily residue.
47
. ' ' -,~ ,
~ ~,
, . . .. . . . .
: . . , :
~Z -
Example XIII
TD a stirrcd and reflw~ g mixture o 35 parts of 4-fluoro-
1,2-benzencdiamine in 270 parts of dimethylbenzenc is addcd dropwise,
during a 2 hours-period, a solution of 57 parts of ethyl a-acetyl-
benzeneacetate in 9û parts of dimethylbe1lzcne while mcantime the
formed water and the ethanol are distilled off (water-separator).
The reactiorl mixture is evaporated and the residue is crystallized
rom 2-propanol. The product is filtered off and purified by column-
chromatography over silica gel using a mixture of trichloromethane
and methanol ( 98.2 by volume) as eluent. The pure fractions are col-
lected and the eluent is evaporated, yielding 11 parts of 6-fluoro-
1, 3-dihydro-1-(1 -methyl-2-phenylethenyl)-2H-benzimidazol-2-one;
mp. 190~C. _ --------- ----- - - -- ~~ -~~ ~ - -
Example XIV
.. . . . . .. . .... . , ~
To a stirred solution o~ 8. 5 parts of 1, 3-dihydro-1-(1-methyl-
e~enyI)-2H-benzimidazol-2-one in 45 parts of N, N-dimethyl-
formarnide are added portionwise 1. 7 parts of a sodium hydride
dispersion 78%. After stirring for 1 hour at room temperature, the
whole is cooled to 0-5C and 8.65 parts of 1-bromo-3-chlo~opropane
are added d~opwise (slowly3. Upon completion, stirring is continued
for 3 hou} s at room temperature. The reaction mixture is poured
ongo <:rushed ice and the product is extracted with methylben7ene. ~;
The extract is washed with water, dried, filtered and evaporated
The residue is crystallized frorn 2-propanol, yielding 5~ 5 parts
(44%~ of 1-(3-chloropropyl)-1,3-dihydro-3-(1-methylethenyl)-
~!H-benzimidazol-2-one; mp 115C;. _ :
. ~
Example XV
To a stirred and hot (55C) mixture of 22. 2 parts of
1, 3-dihydro-5, 6-dimethyl-3~ methyl-2-p~enylethenyl)-2H-
benzirnidazol-2 one, 3 parts of N,N,N-triethylbenzenemethan-
aminium chloride and 112, S paTts o a sodiurn hydroxide solution
60% are added dropwise 15. 8 parts of 1-bromo-3-chloropropane
(~lightly exothermic reaction). Upon completion, stirring is con-
tinued or 5 hours at 55C.'After cooling, water is added and the
oily product is extracted with methylbenzene The extract is
dried, filtered and evaporated. The :residue is cr.ystallized rom
2,2'-oxybispropane, yielding, ater drying, 25 parts (88. 5%)
of 1 -(3-chloropropyl)-1, 3-~ihydro-5, 6-c7.imcth~1-3-(l -methyl-
2-phenylethenyl)-2H-benzirnidazol-2-one; mp, 98C.
4 8
15Z
Example XVI
-
Following the procedure of Example XV and using
equivalent arnounts of the appropriate starting materials there
are prepared:
.
1-(3-chloropropyl)-1, 3-dihydro-3-(2-propenyl) 2H-benz-
imida~ol-2-one as a residue;
1 -(3- chloro-2 -methylpropyl) - 1, 3-dihydro-3 -(1 -methylethenyl) _
2H-benzimidazol-2-one as a residue; and -
1 -(3-chloropropyl)-5 -fluoro-1, 3-dihydro-3 -(1 -methyl-2 -
phe~ylethenyl)-2H-benzimidazol-Z-one as an oily residue.
Example XVII -
: i
.. . A solution of 13 parts of 1-(3-chloropropyl)-1,3-dihydro-3-
(l-methylethenyl)-Z~-benzimidazol-2-one in 6 parts of a hydro-
chloric acid solution and 40 parts of ethano:l is stirred for 2 hours
at room temperature. The reaction mixture is evaporated-and the i ~
. s~lid rèsidue is crystallized from 2-propanol, yielding 9. 5 parts : ~:
(90%) of 1-(3-chloropropyl)-1,3-dihydro-2H-benzi~nidazol-2-one; 5
p 115 C _ ~ .
',~ . ' ' - ' ; ~
' ' ' ' , ' . '~ .
'
,
. ..
~s~
Example XVIII
.. . . ...... . , , , _,, _ _ _ _ _ . _ .. .....
A n~i~ture o~ Z5 parts of 1 (3-chloropropyl)-1, 3-dihydro_
5, 6-dimethyl-3-(i -methyl-2-phenyiethenyl)-2H-benzirnidazol-2-one,
165 parts of a hydrochloric acid solution 6N and 160 parts of ethanol
i6 stirred and refluxed for 6 hours. The reaction mixture is eY~a-
porated and the residue is dissolved in trichloromethane. This
solution is dried, iltered and evaporated. The residue is crystal-
lized from a mixture of Z,2'-oxybispropane and ~-propanol, yielding,
after drying, 16 parts (94.7%~ of 1-(3-chloropropyl)-1,3-dihydro-
5, 6--dîmethyl-2H-benzimidazol-2-one; mp. 140C.
Example XIX
. . . . . .. . ...... . .. . . . . . . .. ......
~ 601ution of l~O parts of 3-~2-nitrophenyl)amino?-1-
propanol in 200 parts of methanol and 100 parts o a hydrochloric
acid solution 10~ is hydrogenated at normal pressure and at a
temperature at 50C, in the presence of 5 parts of palladium-on-
charcoal catalys~ 10%. After the calcuiated amount of hydrogen
(3 moles) is talcen up, hydrogenation is stopped. The catalyst is
filtered off and the filtrate is evaporated. 'rhe residue (mainly
3-,~2-aminophenyl)amin~ propanol hydrochloride) is dissolved
in 500 parts of water. To this sollltion is added a solution of 88. 8
parts of potassium isocyanate in 150 parts of water and the whole
is stirred and refluxed for 15 ho~rs. The reaction mixture is cooled
and the produet is extrac~ced with trichloromethane. The extract is
dTied and evaporated. The residue is dissolved in 250 pa~ts of boiling
water, treated with acti~ated charcoal and crystallized at room tem~
perature. The precipitate is Iiltered of and recrystallized fron
~00 parts of water, followed by recrystallization fronl ethyl acetate,
yieldin~ 5~ parts ~f 1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimida-
zol-2-one hydrate; mp. 48-65 C.
.....
- 50
~858~iiZ
To a solution of 52.5 parts of 1,3-dihydro-1-(3-
hydroxypropyl)~2H-benzimidazol-2-one hydrate in 200 parts of
pyridine is added dropwise 63 parts of methanesulfonyl chloride.
The mixture is stirred and cooled on the air for 2 hours. The
pyridine is evaporated. To the residue is added 500 parts of
water and the formed precipitate is filtered off. It is dis-
solved in 350 parts of trichloromethane. This solution is
dried over magnesium sulfate and evaporated. The residue is
crystallized from 40 parts of methylbenzene, yielding 25.5
parts of 1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-
one methanesulfonate; mp. 118-120C.
To a solution of 0.5 parts of sodium in 40 parts of
absolute ethanol are added in the cold 5.4 parts of 1,3-
dihydro-l-(3-hydroxypropyl)-2H-benzimidazol-2-one methanesulfon-
ate. The whole is stirred until all solid enters solution.
The solution is further stirred and refluxed for 2 hours. After
cooling, the reaction mixture is filtered from some inorganic
matter and the filtrate is evaporated. The residue is dissolved
in 80 parts of methylbenzene, boiled with activated charcoal,
filtered and the filtrate is evaporated again. The solid residue
is washed with cold methylbenzene and crystallized from 16 parts
of methylbenzene, yielding 2.6 parts of 3,4-dihydro-2H-[1,3]-
oxazino[3,2-a]benzimidazole; mp. 116.5-118.5~C.
To a solution of 5.7 parts of 3,4-dihydro-2H-[1,3]-
oxazino[3,2-a]benzimidazole in 80 parts of 2-propanone is added
5.7 parts of iodomethane and the whole is stirred and refluxed
for 2h. 50. Then there is added a second portion of 5.7 parts
of iodomethane and the whole is further stirred and refluxed
for 2h. 50. The solvent is evaporated, yielding 1,3-dihydro-1-
(3-iodopropyl)-3-methyl-2H-benzimidazol-2-one as an oily
residue.
- 51 -
~35E~2
EXAMPLE XX
A mixture of 84 parts of ethyl 4-[(4-chloro-2-nitro-
phenyl)amino]-l-piperidinecarboxylate and 750 parts of a hydro-
bromic acid solution 48% in water is stirred and refluxed for
4 hours. The precipitated product is filtered off, washed with
water and petroleum-ether, and dried, yielding 71 parts (81%)
of N-(4-chloro-2-nitrophenyl)-4-piperidinamine hydrobromide;
mp. 275C.
A mixture of 105 parts of 1-(3-chloropropyl)-1,3-
dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-one, 71 parts
of N-(4-chloro-2-nitrophenyl)-4-piperidinamine hydrobromide,
53 parts of sodium carbonate, 0.2 parts of potassium iodide and
320 parts of 4-methyl-2-pentanone is stirred and refluxed for
24 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, yielding 98.5 parts
(100%) of 1-[3-{4-[(4-chloro-2~nitrophenyl)amino]-1-piperidinyl}-
propyl]-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-one
as a residue.
A solution of 98.5 parts of 1-[3-{4-[(4-chloro-2-
nitrophenyl)amino]-l-piperidinyl}propyl]-1,3-dihydro-3-(1-
methylethenyl)-2H-benzimidazol-2-one in 360 parts of methyl-
benzene is acidified with 2-propanol, previously saturated with
gaseous hydrogen chloride. After boiling for a while, an oil
precipitates. The supernatant phase is decanted and the
residual oil is suspended in water. The suspension is
alkalized with a concentrated ammonium hydroxide solution.
The product is extracted with methylbenzene. The extract is
dried, filtered and evaporated. The residue is crystallized
from 4-methyl-2-pentanone. The product is filtered off and
dried, yielding 68 parts (75.5%) of 1-[3-{4-[(4-chloro-2-
nitrophenyl)amino]-l-piperidinyl}propyl]-1,3-dihydro-2H-
benzimidazol-2-one.
- 52 -
1~5~2
A mixture of 21.5 parts of 1-[3-{4-[t4-chloro-2-
nitrophenyl)amino]-l-piperidinyl}propyl]-1,3-dihydro-2H-benz-
imidazol-2-one and 240 parts of methanol is hydrogenated at
normal pressure and at room temperature with 5 parts of Raney-
nickel catalyst. After the calculated amount of hydrogen is
taken up, the catalyst is filtered off and the filtrate is
evaporated, yielding 20 parts (100~) of 1-[3-{4-[(2-amino-4-
chlorophenyl)amino]-l-piperidinyl}propyl]-1,3-dihydro-2H-
benzimidazol-2-one as a residue.
Example XXI
A mixture of 21.5 parts of 1-[3-{4-[(4-chloro-2-
nitrophenyl)amino]-l-piperidinyl}propyl]-1,3-dihydro-2H-
benzimidazol-2-one and 240 parts of methanol is hydrogenated
at normal pressure and at room temperature with 10 parts of
palladium-on-charcoal catalyst 10%. After the calculated amount
of hydrogen is taken up, the catalyst is filtered off and the
filtrate is evaporated, yielding 18.5 parts (100~) of 1-[3-
{4-[(2-aminophenyl)amino]-1-piperidinyl}propyl]-1,3-dihydro-
2H-benzimidazol-2-one as a residue.
Example XXII
~,
To a stirred mixture of 39.2 parts of 3-(2-nitro-
phenyl)amino-l-propanol and 225 parts of trichloromethane are
added dropwise 35.7 parts of sulfinyl chloride (exothermic
reaction: the temperature rises to 45~C). Upon completion, ~;
stirring is continued for 6 hours at reflux temperature. The
reaction mixture is evaporated, yielding 43 parts (100~) of
N-(3-chloropropyl)-2-nitrobenzenamine as a residue.
53 -
5~
A mixture of 43 parts of N-(3-chloropropyl)-2-nitro-
benzenamine 47.8 parts of 5-chloro-1,3-dihydro-1-(4-piperidinyl)-
2H-benzimidazol-2-one, 30.3 parts of N,N-diethylethanamine and
180 parts of N,N-dimethylacetamide is stirred and heated for
6 hours at 100C. The reaction mixture is cooled and poured
onto 1500 parts of water. The precipitated product is filtered
off, washed with water and with 2,2'-oxybispropane and dried,
yielding 64 parts (78.3%) of 5-chloro-1,3-dihydro-1-{1-[3-(2-
nitrophenylamino)propyl]-4-piperidinyl}-2H-benzimidazol-2-one;
mp. 220C.
A mixture of 64 parts of 5-chloro-1,3-dihydro-1-{1-
[3-(2-nitrophenylamino)propyl]-4-piperidinyl}-2H-benzimidazol-
2-one in 200 parts of methanol and 225 parts of tetrahydrofuran
is hydrogenated at normal pressure and at room temperature with
10 parts of Raney-nickel catalyst. After the calculated amount -
of hydrogen is taken up, the catalyst is filtered off over hyflo ~-
and -the filtrate is evaporated. The residue is crystallized
from a mixture of 2-propanol and ethanol. The product is
filtered off and dried, yielding 42 parts (70.5%) of 1-[1-{3-
[N-(2-aminophenyl)amino]propyl}-4-piperidinyl]-5-chloro-1,3-
dihydro-2H benzimidazol-2-one; mp. 196C.
- 54 -
~35~
Example XXIII
A mixture of 4.6 parts of 1-(3-chloropropyl)-1,3-
dihydro-2H-benzimidazol-2-one, 5 parts of l-(p-fluorophenyl)-
1,3,8-triazaspiro~4,5]decan-4-one, 10 parts of sodium carbon-
ate, 0.2 parts of potassium iodide and 80 parts of 4-methyl-
2-pentanone is stirred and refluxed overnight. After cooling,
the precipitated product is filtered off and triturated twice;
first in a boiling mixture of 4-methyl-2-pentanone and 2-
propanol and then in boiling methanol. It is filtered off
again and crystallized from a mixture of N,N-dimethylform-
amide and water, yielding 4.5 parts of 8-[3~(1,3-dihydro-2-
oxo-2H-benzimidazol-l-yl)propyl]-1-(4-fluorophenyl)-1,3,8-
triazaspiro[4,5]decan-4-one; mp. 215.4C. -~
Example XXIV
Following the procedure of Example XXIII and using
equivalent amounts of the appropriate starting materials the
following compounds are prepared:
8-[3-(6-chloro-2,3-dihydro-2-oxo-lH-benzimidazol-l-yl)propyl]-
1-(4-fluorophenyl)-1,3,8-triazaspiro[4,5]decan-4-one hemi-
hydrate; mp. 233C;
,,,
1-(4-fluorophenyl)-8-[3-(2,3-dihydro-5,6-dimethyl-2-oxo-lH-
benzimidazol-l-yl)propyl]-1,3,8-triazaspiro[4,5]decan-4-one;
mp. 245.2C;
8-{3-r2,3-dihydro-2-oxo-3-(2-propenyl)-lH-benzimidazol-l-yl]-
propyl}-l-phenyl-1,3,8-triazaspiro[4,5]decan-4-one; mp. 114C;
- 55 -
58~Z
8-[3-(2,3-dihydro-2-oxo-lH-benzimidazol-l-yl)propyl]-1-[3-
(trifluoromethyl)phenyl]-1,3,8-triazaspiro[4,5]decan-4-one;
mp. 198.2C;
8-[3-(2,3-dihydro-2-oxo-lH-benzimidazol-l-yl)propyl]-l-
phenyl-1,3,8-triazaspiro[4,5]decan-4-one; mp. 228C;
8-[3-(5-chloro-2,3-dihydro-2-oxo-lH-benzimidazol-l-yl)-
propyl]-l-(4-fluorophenyl)-1,3,8-triazaspiro[4,5]decan-4-one;
mp. 171.7C;
8-[3-(6-chloro-2,3-dihydro-2-oxo-lH-benzimidazol-l-yl)-
propyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one;
mp. 255-256C;
1-(4-fluorophenyl)-8-{3-~2,3-dihydro-2-oxo-5-trifluoromethyl)-
lH-benzimidazol-l-yl]-propyl}-1,3,8-triazaspiro[4,5]decan-4-
one; mp. 259.7C;
8-[3-(2,3-dihydro-2-oxo-lH-benzimidazol-l~yl)propyl]-3-
methyl-l-phenyl-1,3,8-triazaspiro[4,5]decan-4-one; mp. 186C;
1-(4-chloro-3-methylphenyl)-8-[3-(2,3-dihydro-2-oxo-lH-
benzimidazol-l-yl)propyl]-1,3,8-triazaspiro[4,5]decan-4-
one; mp. 208.6C; and
8-[3-(lH-benzimidazol-l-yl)propyl]-l-phenyl-1,3,8-triazaspiro-
[4,5]decan-4-one; mp. 191C.
- 56 -
Example XXV
A mixture of 4.2 parts of 4 chloro-1,3-dihydro-3-
(3-hydroxypropyl)-2H-benzimidazol-2-one methanesulfonate, 2.5
parts of l-phenyl-1,3,8-triazaspiro[4,5]decan-4-one, 10 parts
of sodium carbonate and 80 parts of 4-methyl-2-pentanone is
stirred and refluxed overnight. The reaction mixture is
cooled and water is added. The precipitated product is
filtered off and crystallized twice from a mixture of N,N-
dimethylformamide and water, yielding 0.8 parts (17%) of
8-~3-(7-chloro-1,3-dihydro-2-oxo-2H-benzimidazol-l-yl)propyl]-
1 phenyl-1,3,8-triazaspiro[4,5]decan-4-one; mp. 258.4C.
Example XXVI
Following the procedure of Example XXV and by
carrying out the reaction in N,N-dimethylformamide as a
solvent, the following compounds are prepared from the
appropriate starting materials:
8-[3 (5-chloro-2,3-dihydro-2-oxo-lH benzimidazol-l-yl)-
propyl]-l-phenyl-1,3,8-triazaspiro[4,5]decan-4-one;
mp. 233.7C; and
8-[3-(2,3-dihydro-5-methyl-2-oxo-lH-benzimidazol-l-yl)-
propyl]-l-phenyl-1,3,8-triazaspiro[4,5]decan-4-one; mp.
255.5C.
- 57 -
S8~2
Example XXVII
A mixture of 5 parts of 1,3-dihydro-1-(3-iodopropyl)-
3-methyl-2H-benzimidazol-2-one, 3.4 parts of 1-phenyl-1,3,8-
triazaspiro[4,5]decan-4-one, 2.65 parts of sodium carbonate
and 22.5 parts of N,N-dimethylformamide is stirred and heated
for 2 hours at 70C. The reaction mixture is cooled and
poured onto water, whereupon an oily precipitate is formed.
The supernatant aqueous phase is decanted and the residual
oil is dissolved in trichloromethane. The solution is dried,
filtered and evaporated. The residue is purified by column-
chromatography over silica gel using a mixture of trichloro-
methane and 5% of methanol as eluent. The pure fractions
are collected and the eluent is evaporated, yielding 1 part
of 8-[3-(1,3-dihydro-3-methyl-2-oxo-2H-benzimidazol-1-yl)
propyl]-l-phenyl-1,3,8-triazaspiro[4,5]decan-4-one; mp.
164.4C.
Example XXVIII
A mixture of 8 parts of 5,6-dichloro-1,3-dihydro-1-
(3-hydroxypropyl)-2H-benzimidazol-2-one methanesulfonate,
9.2 par-ts of 1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one and
90 parts of N,N-dimethylformamide is stirred and heated at
60C for one hour. The reaction mixture is evaporated and
water is added to the residue. The whole is alkalized with
ammonium hydroxide and the product is extracted with trichloro-
methane. The extract is dried, filtered and evaporated. The
residue is purified by column-chromatography over silica gel
using a mixture of trichloromethane and 10~ of methanol as
eluent. The pure fractions are collected and the eluent is
evaporated. The solid residue is triturated in 4-methyl-2-
pentanone. The product is filtered off and dried, yielding
2 parts of 8-[3-(5,6-dich]oro-1,3-dihydro-2-oxo-2H-benzimida-
zol-l-yl)propyl]-l-phenyl-1,3,8-triazaspiro[4,5]decan-4-one;
mp. 275.2C.
- 58 -
s~æ
Example XXIX
A mixture of 2.3 parts of 1-(3-chloropropyl)-1,3-
dihydro-2H-benzimidazol-2-one, 2.5 parts of 5-chloro-1,3-
dihydro-l-(4-piperidinyl)-2H-benzimidazol-2-one, 3.2 parts
of sodium carbonate, 0.1 parts of potassium iodide and 80
parts of 4-methyl-2-pentanone is stirred and refluxed for
24 hours. The reaction mixture is cooled to room temperature
and water is added. The undissolved produc-t is fil-tered off
and purified by column-chromatography over silica gel using
a mixture of trichloromethane and 10% of methanol as eluent.
The pure fractions are collected and the eluent is evaporated.
The residue is crystallized from 4-methyl-2-pentanone. The
product is filtered off and recrystallized from a mixture of `
N,N-dimethylformamide and water, yielding 1.3 parts (30~)
of 5-chloro-1-{-1[3-(1,3-dihydro-2-oxo-2H-benzimidazol-l-
yl)propyl]-4-piperidinyl}-1,3-dihydro-2H-benzimidazol-2-one;
mp. 242.5C.
Example XXX
Following the procedure of Example XXIX and using
equivalent amounts of the appropriate starting materials, the
following compounds are prepared:
5-chloro-1-[1-{3-[2,3-dihydro-3-(1-methylethenyl)-2-oxo-lH-
benzimidazol-l-yl]-2-methylpropyl}-4-piperidinyl]-1,3-dihydro-
2H-benzimidazol-2-one as an oily residue;
6-chloro-1-{3-[4~(5-chloro-2,3-dihydro-2-oxo-lH-benzimidazol-
l-yl)-l-piperidinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one
hydrate; mp. 179.6C;
- 59 -
35~
1-{3-[4-(2,3-dihydro 2-oxo-lH-benzimidazol-l-yl)-l-piperidinyl~-
propyl}-1,3-dihydro-5,6-dimethyl-2H-benzimidazol-2-one 2-
propanolate; mp. 159C;
6-chloro-1,3-dihydro-1-{3-[4-(2,3-dihydro-2-oxo-lH-benzimida-
zol-l-yl)-l-piperidinyl]propyl}-2H-benzimidazol-2-one;
mp. 273C;
1-{3-[4-(2,3-dihydro-2-oxo-lH-benzimidazol-l-yl)-1-piperidinyl]-
propyl}-1,3-dihydro-2H-benzimidazol-2-one; mp. 225C;
1,3-dihydro-1-{3-[4-(2,3-dihydro-2-oxo-lH-benzimidazol-l-yl)-
1-piperidinyl]propyl}-5-(tri~luoromethyl)-2H-benzimidazol-2-
one; mp. 263.4C;
5-chloro-1-{3-[4-(2,3-dihydro-2-oxo-lH-benzimidazol-l-yl)-
l-piperidinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one; mp.
253-255C;
5-chloro-1-[1-{3-[2,3-dihydro-2-oxo-3-(2-propenyl)-lII-benz-
imidazol-l-yl]propyl}-4-piperidinyl]-1,3-dihydro-2H-benz-
imidazol-2-one; mp. 153.4C;
1-{3-[3,6-dihydro-2-(2,3-dihydro-2-oxo-lH-benzimidazol-l-yl)-
1-(2H)-pyridinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one;
mp. 206.6C;
5-chloro-1-[1-{3-[2,3-dihydro-3-(1-methylethenyl)-2-oxo-lH-
benzimidazol-l-yl]propyl}-4-piperidinyl]-1,3-dihydro-2H-
benzimidazol-2-one; mp. 165.2C; and
1-{1-[4-(lH-benzimidazol-l-yl)butyl]-4-piperidinyl}-1,3
dihydro-2H-benzimidazol-2-one; mp. 157.1C.
- 60 -
~L~t3S~3~2
Example XXXI
A mixture of 5.3 parts of 1-(3-chloropropyl)-1,3-di-
hydro-5-methyl-3-(1-methylethenyl)-2H-benzimidazol-2-one, 4.3
parts of 1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one,
6.4 parts of sodium carbonate and 200 parts of 5-methyl-2-
pentanone is stirred and refluxed overnight with water-
separator. After cooling, water is added and the layers are
separated. The 4-methyl-2-pentanone-phase is dried, filtered
and evaporated. The oily residue is purified by column-
chromatography over silica gel using a mixture of trichloro-
methane and methanol (90:10 by volume) as eluent. The pure
fractions are collected and the eluent is evaporated, yielding
6 parts (67%) of 1-{3-~4-(2,3-dihydro-2-oxo-lH-benzimidazol-l-
yl)-l-piperidinyl~propyl}-1,3-dihydro-5-methyl-3-(1-methyl-
ethenyl)-2H-benzimidazol-2-one as an oily residue.
Example XXXII
Following the procedure of Example XXXI and using
equivalent amounts of the appropriate starting materials,
the following compounds are prepared:
1-{3-[4-(5-chloro-2,3-dihydro-2-oxo-lH-benzimidazol-l-yl)-l-
piperidinyl]propyl}-1,3-dihydro-5-methyl-3-(1-methylethenyl)-
2H-benzimidazol-2-one as an oily residue;
3-{3-[4-(5-chloro-2,3-dihydro-2-oxo-lH-benzimidazol-l-yl)-
l-piperidinyl]propyl}-1,3-dihydro-5-methyl-1-(1-methylethenyl)-
2H-benzimidazol-2-one as an oily residue;
1-{1-[3-(lH-benzimidazol-l-yl)propyl]-4-piperidinyl}-5-chloro-
1,3-dihydro-2H-benzimidazol-2-one; mp. 224C; and
- 61 -
35852
5-chloro-l-{l-[3-(2-oxo-3(2H)-benzoxazolyl)propyl]-4-
piperidinyl}-1,3-dihydro-2H-benzimidazol-2-one; mp. 212.3C.
Example XXXIII
A mixture of 5.4 parts of 3-~3-bromopropyl)-2(3H)-
benzothiazolone, 4.5 parts of 5-chloro-1,3-dihydro-l-(4-
piperidinyl)-2H-benzimidazol-2-one, 5.3 parts of sodium carbon-
ate, 0.1 parts of potassium iodide and 200 parts of 4-methyl-
2-pentanone is stirred and refluxed for 3 hours with water-
separator. After cooling, 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-
pentanone and 2-propanone. The product i5 filtered off and
dried, yielding 2.5 parts (31%) of 5-chloro-1,3-dihydro-l-
{1-[3-(2-oxo-2(2H)-benzothiazolyl)propyl]-4-piperidinyl}-2H-
benzimidazol-2-one; mp. 184.1C.
Example XXXIV
. . _
Following the procedure of Example XXXIII there is
prepared l-{l-[3-(lH-benzotriazol-l-yl)propyl~-4-piperidinyl}-
5-chloro-1,3-dihydro-2H-benzimidazol-2 one; mp. 203.4C by
reaction of 1-(3-bromopropyl)-lH-benzotriazole with 5-chloro-
1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one.
- 62 -
85~3~2
Example XXXV
A mixture of 5 parts of 1,3-dihydro-1-(3-iodopropyl)-
3-methyl-2H-benzimidazol-2-one, 3.75 parts of 5-chloro-1,3-
dihydro-l-(4-piperidinyl)-2H~benzimidazol-2-one, 2, 65 parts
of sodium carbonate and 22.5 parts of N,N-dimethylformamide
is stirred at 70-80C for 2 hours. The reaction mixture is
cooled, poured onto water and the precipitated product is
filtered off. It is dissolved in trichloromethane. The
solution is dried, filtered and evaporated. The residue is
crystallized from 4-methyl-2-pentanone, yielding 3 parts
(43%) of 5-chloro-1{1-[3-(1,3-dihydro-3-methyl-2-oxo-2H-
benzimidazol-l-yl)propyl]-4-piperidinyl}-1,3-dihydro-2H-
benzimidazol-2-one; mp. 166.5C.
Example XXXVI
A mixture of 7.6 parts of 5-chloro-1,3-dihydro-1-
(3-hydroxypropyl)-2H-benzimidazol-2-one methanesulfonate,
5.5 parts of 5-chloro-1,3-dihydro-1-(4-piperidinyl)-2H-
benzimidazol-2-one, 5 parts of sodium carbonate and 63 parts
of N,N-dimethylformamide is stirred and heated in an oil-
bath at 50-60C for 2 hours. The reaction mixture is poured
onto water. The precipitated product is filtered off, dried
and purified by column-chromatography over silica gel using
a mixture of trichloromethane and 10~ of methanol as eluent.
The pure Eractions are collected and the eluent is evaporated.
The solid residue is crystallized from 4-methyl-2-pentanone.
The product is filtered off and recrystallized from a mixture
of N,N-dimethylformamide and water. It is filtered off again
and dissolved in a mixture of 4-methyl-2-pentanone and a small
amount of N,N-dime-thylformamide. The solution is filtered
till clear and the filtrate is concentrated to a volume of
about 10 parts. The concentrate is triturated in methanol.
The precipitated product is filtered off and dried, yielding
1.27 parts of 5-chloro-1-{3-~4-~5-chloro-1,3-dihydro-2-oxo-2H-
benzimidazol-l-yl)-l-piperidinyl]propyl}-1,3-dihydro-2H-benz-
imidazol-2-one; mp. 229-236C.
- 63 -
~L~15 5~5;2
Example XXXVII
A mixture of 7 parts of 1-(3-chloropropyl)-5-fluoro-1,
3-dihydro-3-(1-methyl)-2-phenylethenyl)-2H-benzimidazol-2-one,
5-parts of 5-chloro-1,3-dihydro-1-(4-piperidinyl)-2H-benzi-
midazol-2-one, 4.25 parts of sodium carbonate, 0.1 parts of
potassium iodide and 200 parts of 4-methyl-2-pentanone is
stirred and refluxed overnight. The mixture is cooled to room
temperature, water is added and the layers are separated. The
organic phase is dried, filtered and evaporated. The residue
is stirred and refluxed overnight with a solution of 55 parts
of a hydrochloric acid solution 6N in 40 parts of ethanol.
The solvent is evaporated and the residue is taken up in water.
The whole is alkalized with ammonium hydroxide and the product
is extracted with trichloromethane. The extract is dried,
filtered and evaporated. The residue is purified by column- -
chromatography over silica gel using a mixture of trichloro-
methane and methanol (95:5 by volume) as eluent. The pure
fractions are collected and the eluent is evaporated. The
residue is converted into the hydrochloride salt in 2-propanol.
The salt is filtered off and dried, yielding 1.2 parts of 1-
{3-[4-(5-chloro-2,3-dihydro-2-oxo-lH-benzimidazol-l-yl)-l-
piperidinyl]propyl}-5-fluoro-1,3-dihydro-2H-benzimidazol-2-
one hydrochloride hydrate; mp. 250C.
Example XXXVIII
Following the procedure of Example XXXVII there are
prepared:
5-chloro-1-{1-[4-(2,3-dihydro-2-oxo-lH-benzimidazol-l-yl)-
butyl]-4-piperidinyl}-1,3-dihydro-2H-benzimidazol-2 one
hemihydrate; mp. 258C by the reaction of 1-(4-chlorobutyl)-
1,3-dihydro-2-(1-methylethenyl)-2H-benzimidazol-2-one with
5-chloro-1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one;
and
- 64 -
~ 3585z
1-{1-[3-(2,3-dihydro-2-oxo-lH-benzimidazol-l-yl)propyl]-4-
piperidinyl}-1,3-dihydro-3-(1-methylethyl)-2H-benzimidazol-
2-one; mp. 174.3C, by the reaction of 1-(3-chloropropyl)-
1,3-dihydro-2~ methylethenyl)-2H-benzimidazol-2-one with
1-(1-methylethyl)-3-(4-piperidinyl)-2H-benzimidazol-2-one.
Example XXXIX
A mlxture of 6 parts of 1-{3-~4-(2,3-dihydro-2-oxo-
lH-benzimidazol-l-yl)-l-piperidinyl]propyl}-1,3-dihydro-5-
methyl-3-(1-methylethenyl)-2H-benzimidazol-2-one, 12 parts of
a hydrochloric acid solution, 30 parts of water and 40 parts
of ethanol is stirred first for a while at 50C and further ;-
for 1 hour at room temperature. The reaction mixture is
evaporated and the residue is crystallized from a mixture of
4-methyl-2-pentanone and 2-propanol. The product is filtered
off and dried, yielding 3.7 parts (40%) of 1-{3-[4-(2,3-
dihydro-2-oxo-lH-benzimidazol-l-yl)-l~piperidinyl]propyl}-1,3-
dihydro-5-methyl-2H-benzimidazol-2-one hydrochloride hydrate;
mp. 251.4C. ~`
Example XL
Following the procedure of Example XXXIX the following
compounds are deri~ed from the corresponding (l-methylethenyl)-
substituted analogs:
5-chloro-1-{1-[3-(2,3-dihydro-5-methyl-2-oxo-lH-benzimidazol- ~
l-yl)propyl]-4-piperidinyl}-1,3-dihydro-2H-benzimidazol-2-one
hydrochloride hydrate; mp. 213.3C;
5-chloro-1-{1-[3-(2,3-dihydro-6-methyl-2-oxo-lH-benzimidazol-
l-yl)propyl]-4-piperidinyl}-1,3~dihydro-2H-benzimidazol-2-one
hemihydrate; mp. 195.4C; and
- 65 -
~B5~352
5-chloro-1-{1-[3-(2,3-dihydro-2-oxo-lH-benzimidazol-l-yl)-2-
methylpropyl]-4-piperidinyl}-1,3-dihydro-2H-benzimidazol-2-
one; mp. 244C.
Example XLI
A mixture of 38 parts of carbon disulfide, 6 parts
of 1-[1-{3-[M-(2-aminophenyl)amino]propyl}-4-piperidinyl]-5-
chloro-1,3-dihydro-2H-benzimidazol-2-one and 32 parts o~
ethanol is stirred and refluxed for 24 hours. The reaction
mixture is evaporated and the residue is crystallized from
ethanol. The product is filtered off and recrystallized from
a mixture of N,N-dimethylformamide and water, yielding 3 parts
(45.5%) of 5-chloro-1-{1~[3-(2,3-dihydro-2-thioxo-lH-benzi-
midazol-l-yl)propyl]-4-piperidinyl}-1,3-dihydro-2H-benzimidazol-
2-one; mp. 266.6C.
Example XLII
A mixture of 4 parts of 1-[1-{3-[N-(2-amino-5-chloro-
phenyl)amino]propyl}-4-piperidinyl]-1,3-dihydro-2H-benzimid-
azol 2-one, 6 parts of a concentrated hydrochloric acid solu- ;
tion and 30 parts of formic acid is stirred and refluxed over-
night. The reaction mixture is evaporated and water is added
to the residue. The whole is alkalized with a diluted ammonium
hydroxide solution and the product is extracted with trichloro-
methane. The extract is dried, filtered and evaporated. The ~-
residue is crystallized from 4-methyl-2-pentanone. The product
is filtered off and recrystallized from 2-propanol, yielding
1.1 parts (27%) of 1-{1-~3-(6-chloro-lH-benzimidazol-l-yl)-
propyl]-4-piperidinyl}-1,3-dihydro-2H-benzimidazol-2-one; mp.
214.9C.
- 66 -
~585~
Example XLIII
:i
A mixture of 20 parts of 1-[3-{4-[(2-amino-4-chloro-
phenyl)amino]-l-piperidinyl}propyl]-1,3-dihydro-2H-benzimidazol-
2-one, 52 parts of carbon disulfide and 120 parts of ethanol is
stirred and refluxed for 24 hours. The reaction mixture is
filtered after cooling, and the filtrate is evaporated. The
residue is crystallized from 2-propanol. The product is filtered
off and recrystallized from ethanol, yielding, after drying,
7.5 parts (34%) of 1-{3-[4-(5-chloro-2,3-dihydro-2-thiozo-lH-
benzimidazol-1-yl)-1-piperidinyl]propyl}-1,3-dihydro-2H-
benzimidazol-2-one; mp. 254.3C.
,
Example XLIV ~-
Following the procedure of Example XLIII there is
prepared 1-{3-[4-(2,3-dihydro-2-thioxo-lH-benzimidazol-l-
yl)-l-piperidinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one;
mp. 248.5C by the reaction of 1-[3-{4-[(2-aminophenyl)amino]-
l-piperidinyl}propyl]-1,3-dihydro-2H--benzimidazol-2-one with
carbon disulfide.
Example XLV
~: .
A mixture of 2~21 parts of 1-{3-[4-(5-chloro-2,3-
dihydro~2-thioxo-lH-benzimidazol-l-yl)-l-piperidinyl]propyl}-l,
3-dihydro-2H-benzimidazol-2-one, 0.71 par~s of iodomethane,
0.28 parts of sodium methanolate and 40 parts of methanol is
stirred overnight at room temperature. The reaction mixture
is evaporated. The residue is stirred with water and the
product is extracted with trichloromethane. The extract is
dried, filtered and evaporated. The residue is crystallized
from 4-methyl-2-pentanone. The product is filtered off and
dried, yielding 1.1 parts of 1-[3-{4-[5-chloro-2-(methylthio)-
lH-benzimidazol-l-yl]-l-piperidinyl}propyl]-1,3-dihydro-2H-
benzimidazol-2-one; mp. 196.1C.
- 67 -
~35~5~: :
Example XLVI
A mixture of 5 parts of 5-chloro-1-{1-[3-(2,3-dihydro-
2-oxo-lH-benzimidazol-l-yl)propyl]-4-piperidinyl}-1,3-dihydro-
2H-benzimidazol-2-one, 10 parts of acetic acid anhydride and
90 parts of methylbenzene is stirrred and refluxed overnight.
The reaction mixture is cooled, water is added and the whole is
alkalized with a diluted sodium carbonate solution. The layers
are spearated and the organic phase is dried, filtered and
evaporated. The residue is crystallized from methylbenzene.
The product is filtered off and recrystallized from methyl-
benzene, yielding 4.5 parts of 3-acetyl-5-chloro-1-{1-[3-(3-
acetyl-2,3-dihydro-2-oxo-lH-benzimidazol-l-yl)propyl]-4-
piperidinyl}-1,3-dihydro-2H-benzimidazol-2-one; mp. 185.3C.
Example XLVII
To a stirred solution of 1 part of 5-chloro-1-{1-[3-
(1,3-dihydro-2-oxo-2H-benzimidazol-l-yl)propyl]-4-piperidinyl}-
1,3-dihydro-2H-benzimidazol-2-one in 32 parts of ethanol is
added a solution of 0.35 parts of (+)-2,3-dihydroxy-1,4-
butanedioic acid in 8 parts of ethanol. Upon stirring, the
product is allowed to crystallize. It is filtered off and
dried, yielding 1 part of (+~-5-chloro-1-{1-[3-(1,3-dihydro-2-
oxo~-2H-benzimidazol-l-yl)propyl]-4-piperidinyl}-1,3-dihydro-2H-
benzimidazol-2-one 2,3-dihydroxybutanedioate, ethanolate; mp.
153.5C
Example XLVIII
.
A stirred solution of 1 part of 5-chloro-1-{1-[3-(1,
3-dihydro-2-oxo-2H-benzimidazol-1-yl)propyl]-4-piperidinyl}-1,
3-dihydro-2H-benzimidazol-2-one in 20 parts of ethanol is
saturated with gaseous hydrogen chloride. The formed hydro-
chloride salt is allowed to crystallize while stirring. It
is filtered off and dried, yielding 0.6 parts (53%) of 5-chloro-
1-{1-[3-(1,3-dihydro-2-oxo-2H-benzimidazol-l-yl)propyl]-4-
piperidinyl}-1,3-dihydro-2H-benzimidazol-2-one hydrochloride
hydrate; mp. 195.7C.
- 68 -
s~ ~
Example IL
..
A solution of 1 part of 5-chloro-1-{1-[3~(1,3-dihydro-
2-oxo-2H-benzimidazol-l-yl)propyl]-4-piperidinyl}-1,3-dihydro-
2H-benzimidazol-2-one in 40 parts of ethanol is acidified with
2-propanol, previously saturated with gaseous hydrogen chloride.
While cooling, the formed hydrochloride salt is allowed to
crystallize, yielding 1 part (83%) of 5-chloro-1-{1-[3-(1,3-
dihydro-2-oxo-2H-benzimidazol-l-y])propyl]-4-piperidinyl}-1,3-
dihydro-2H-benzimidazol-2-one hydrochloride ethanolate; mp.
213.7C.
Example L
10.2 Parts of 5-chloro-1-{1-[3-(2,3-dihydro-2-oxo-
lH-benzimidazol-l-yl)propyl]-4-piperidinyl}-1,3-dihydro-2H-
benzimidazol-2-one are converted into the (+)-2,3-dihydroxy-
butanedioate salt in 100 parts of water at reflux temperature.
The solution is treated for 10 minutes with a mixture of 0.5
parts of activated charcoal and 0.2 parts of hyflo. The latter
is filtered off over hyflo and the filtrate is cooled till an
oily precipitate is formed. The oily product solidifies upon
heating for a while. The whole is allowed to cool to room
temperature and stirred for 3 hours at this temperature. The -~
product is filtered off, washed with water and dried in vacuo ~-~
for 18 hours at 60C, yielding 10.24 parts (85.3%) of 5-chloro-
1-{1-[3-(2,3-dihydro-2-oxo-lH-benzimidazol-l-yl)propyl]-4-
piperidinyl}-1,3-dihydro-2H~benzimidazol-2-one hemi-[R-(R ,R )]
(+)-2,3-dihydroxybutanedioate hydrate; mp. 184.1C [~] = +5.13
(c = 1% CH30H).
- 69 -
~85~35Z
Example LI
A mixture of 6.7 parts of 5-chloro-1,3-dihydro-1-
(3-hydroxypropyl)-2H-benzimidazol-2-one methanesulfonate,
4O2 parts of 4-(4~chlorophenyl)-4-piperidinol, 3.2 parts of
sodium carbonate and 32 parts of 4-methyl-2-pentanone is
stirred and heated at 50-60~C for 1.50 hours. The reaction
mixture is poured onto ice-water. The precipitated product
is filtered off and dissolved in trichloromethane. The solu-
tion is washed with water, dried, filtered and evaporated.
The solid residue is purified by column-chromatography over
silica gel using a mixture of trichloromethane and 10% of ;
methanol as eluent. The pure fractions are collected and the
eluent is evaporated. The solid residue is stirred in a small
amount of trichloromethane. The product is filtered off and
crystallized from 4-methyl-2-pentanone, yielding 2 parts (24%) ~
of 5-chloro-1-{3-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]- -
propyl}-1,3-dihydro-2H-benzimidazol-2-one; mp. 190.8C.
Example LII
A mixture of 3.58 parts of 1-(3-chloropropyl)-1,3-
dihydro-5,6-dimethyl-2H-benzimidazol-2-one, 3.17 parts of
4-(4-chlorophenyl)-4-piperidinol, 5.3 parts of sodium carbon-
ate, 0.2 parts of potassium iodide and 160 parts of 4-methyl-
2-pentanone is stirred and refluxed for 24 hours with water-
separator. After cooling, water is added and the layers are
separated. The organic phase is dried, filtered and evaporated.
The residue is converted into the hydrochloride salt in meth-
anol and 2-propanol. The salt i5 filtered off and dried,
yielding 1.7 parts of 1-{3-[4-(4-chlorophenyl)-4-hydroxy-1-
piperidinyl]propyl}-1,3-dihydro-5,6-dimethyl-2H-benzimidazol-
2-one hydrochloride; mp. 260.8C.
`.
- 70 -
58~2
Example LIII
A mixture of 2.3 parts of 1-(3-chloropropyl)-1,3-
dihydro-2H-benzimidazol 2-one, 2.12 parts of 4-(4-chlorophenylj-
4-piperidinol, 3.2 parts of sodium carbonate, 0.1 parts of
potassium iodide and 80 parts of 4-methyl-2-pentanone is
stirred and refluxed for 36 hours. After cooling to room
temperature, water is added and the layers are separated. The
organic phase is dried, filtered and evaporated. The residue
is purified by column-chromatography over silica gel using a
mixture of trichloromethane and 10% of methanol as eluent.
The pure fractions are collected and the eluent is evaporated.
The residue is crystallized from methylbenzene, yielding ~
1 part (26%) of 1-{3-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]- -;
propyl}-1,3-dihydro-2H-benzimidazol-2-one; mp. 134.2C.
~xample LIV
Following the procedure of Example LIII and using
equivalent amounts of the appropriate starting materials, the
following compounds are prepared:
:~ ,
6-chloro-1-{3-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]-
propyl}-1,3-dihydro-2H-benzimidazol-2-one; mp. 180.6C;
1-[3-{4-[4-chloro-2-(trifluoromethyl)phenyl]-4-hydroxy-1-pi-
peridinyl}propyl]-1,3-dihydro-2H-benzimidazol-2-one; mp.
189.2C;
.: ;
1-{3-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]propyl}-1,3-
dihydro-2-(2-propenyl)-2H-benzimidazol-2-one; mp. 141.3C;
,~ ~
1-{4-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl~butyl}-1,3-
dihydro-2H-benzimidazol-2-one; mp. 160.6~C; and
1-[3-(lH-benzimidazol-l-yl)propyl]-4-(4-chlorophenyl)-4-
piperidinol; mp. 160C.
~5~3SZ
Example LV
A mixture of 5 parts of 1-(3-chloropropyl)-1,3-di-
hydro-3-(1-methylethenyl)-2H-benzîmidazol~2-one, 3.9 parts
of 4-(4-fluorophenyl)-4-piperidinol, 5.3 parts oE sodium car-
bonate and 80 parts of 4-methyl-2-pentanone is stirred and
refluxed for 48 hours with water-separator. The reaction
mixture is cooled to room temperature, water is added and the
whole is alkalized with 15 parts of a sodium hydroxide solution
60%. The layers are separated and the organic phase is dried,
filtered and evaporated. The residue is purified by column-
chromatography over silica gel using a mixture of trichloro-
methane and 10~ of methanol as eluent. The pure fractions
are collected and the eluent is evaporated. The oily residue
is dissolved in 2-propanone. The solution is acidified with
2-propanol, previously saturated with gaseous hydrogen chloride,
and the whole is stirred and refluxed for 15 minutes. The
solvent is evaporated and the formed hydrochloride salt is
dissolved in water. The free base is liberated in the con-
ventional manner with a diluted sodium hydroxide solution.
The product is extracted with 4-methyl-2-pentanone~ The ex-
tract is dried, filtered and evaporated. The residue is
crystallized from methylbenzene. The product is filtered off
and dried, yielding 2.5 parts of 1-{3-[4-(4-fluorophenyl)-4-
hydroxy-l-piperidinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-
one; mp. 135.4~C.
Example LVI
Following the procedure of Example XXIII and using
equiva~ent amounts of the appropriate starting materials the
following compounds are still obtained.
1-(4-chlorophenyl)-8-[3-(1,3-dihydro-2-oxo-2H-benzimidazol-l-
yl)propyl]-1,3,8-triazaspiro[4,5]decan-4-one;
1-(4-chlorophenyl)-8-[3-(5-chloro-1,3-dihydro-2-oxo-2H-benzimid-
azol-l-yl)propyl]-1,3,8-triazaspiro[4,5]decan-4-one;
8-[3-(1,3-dihydro-2-oxo-2H-benzimidazol-l-yl)-2-methylpropyl]-
1-(4-fluorophenyl)-1,3,8-triazaspiro[4,5]decan-4-one;
358~i2
8-[3-(1,3-dihydro-2-oxo-2H-benzimidazol-l-yl)-propyl]-l-
(4-fluorophenyl)-3-methyl-1,3,8-triazaspiro[4,5]decan-4-one; :
and
8-[3-(1,3-dihydro-2-oxo-2H-benzimidazol-l-yl)propyl]-3-ethyl-
1-(4-fluorophenyl)-1,3,8-triazaspiro[4,5]decan-4-one.
Example LVII :
Following the procedure of Example XXIX and using
equivalent amounts of the appropriate starting materials,
the following compounds are still obtained:
'-
5-chloro-1-{3-[4-(1,3-dihydro-5-methyl-2-oxo-2H-benzimidazol-
l-yl)-l-piperidinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one;
5-chloro-1-[3-{4-[1,3-dihydro-2-oxo-5-(trifluoromethyl)-2H-
benzimidazol-l-yl]-l-piperidinyl}propyl]-1,3-dihydro-2H-benz- ~-
imidazol-2-one;
1-{3-[4-(5,6-dichloro-1,3-dihydro-2-oxo-2H-benzimidazol-l-yl)- ~:
l-piperidinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one;
5-chloro-1-{3-[4-(5-chloro-1,3-dihydro-2-oxo-2H-benzimidazol-
l-yl)-l-piperidinyl]-2-methylpropyl}-1,3-dihydro-2H-benzimidazol-
2-one;
5-bromo-1{3-[4-(5-chloro-1,3-dihydro-2-oxo-2H-benzimidazol-l-
yl)-l-piperidinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one;
; and
.
1-{3-[4-(5-bromo-1,3-dihydro-2-oxo-2H-benzimidazol-l-yl)-l-
piperidinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one.
,
~L~8585Z
Example LVII
Following the procedure of Example LIII and using
e~uivalent amounts of the appropriate starting materials, the
following compounds are still obtained:
5-chloro-1-[3-{4-[4-chloro-3-(trifluoromethyl)phenyl]-4-
hydroxy-l-piperidinyl}propyl]-1,3-dihydro-2H benzimidazol-2-
one;
5-chloro-1{3~[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]-2-
methylpropyl}-1,3-dihydro-2H-benzimidazol-2-one;
5-bromo-1-{3-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]propyl}- .
1,3-dihydro-2H~benzimidazol-2-one;
1-{3-[4-(4-bromophenyl)-4-hydroxy-1-piperidinyl]propyl}-1,3-
dihydro-2H-benzimidazol-2-one;
:
1-{3-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]propyl}-1,3-
dihydro-5-(trifluoromethyl)-2H-benzimidazol-2-one; ~
1-{3-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]propyl}-5,6- ~.
dichloro-1~3-dihydro-2H-benzimidazol-2-one; and :
5-chloro-1-{3-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]-
propyl}-1,3-dihydro-3-(2-propenyl)-2H-benzimidazol-2-one.
..
~ r
- 74 -
