Note: Descriptions are shown in the official language in which they were submitted.
21141 1~
-- 1
60675.573
Five-membered heterocvcles
This invention relates to novel five-membered
heterocycles, their preparation, pharmaceutical
compositions containing them and their use.
It has been found that certain novel five-membered
heterocycles have valuable pharmacological properties,
particularly aggregation-inhibiting effects.
Thus viewed from one aspect the present invention
provides a compound of formula I
Xl
X2' X5 (1)
X3 X4
(wherein:
(i) with the proviso that the five-membered
heterocyclic ring is not a pyrrolidine, pyrroline,
pyrrolinone or pyrrolidinone ring and contains at least
one carbon atom and
(ii) with the exception of the compounds 3-(4-amidino-
phenyl)-l-[4-(2-amino-2-carboxyethyl)-phenyl]-2H-
pyrazol-5-one and 3-(4-amidinophenyl)-l-[4-(2-amino-2-
methoxycarbonyl-ethyl)-phenyl]-2H-pyrazol-5-one,
a first of the groups X~, X2, X3, X4 and X5 is a group of
formula
A - B - C' - N< ,
A - B - C' - CH< or
A - B - C' - C~
- 2 - 21~178
(wherein
A denotes a pyridyl or quinuclidinyl group,
or a C57-cycloalkyl group optionally substituted by 1 to
4 a].kyl groups, by a hydroxy, alkoxy, phenylalkoxy,
cyano, aminocarbonyl, carboxy, alkoxycarbonyl or
phenylalkoxycarbonyl group, in which an unsubstituted
ring methylene group is replaced by an Ra-N~ group,
.
and, additionally, in a 6- or 7-membered azacycloalkyl
group thus formed a >CH- unit in the 4-position is .
optionally replaced by a nitrogen atom, or in a 5- to 7-
membered azacycloalkyl group thus formed a -CH2-CH< unit ~ :
is optionally replaced by a -CH=C< unit, and in a
piperazinyl or homopiperazinyl ring thus formed a
methylene group, which is adjacent to the nitrogen atom :
in the 4-position, is optionally replaced by a carbonyl
group,
or, if D denotes a C18-alkylene or C18-alkenylene group
substituted by a R3R4N-C0-NR5- or R6-S02-NR3- group
(wherein R3, R4 and R5 independently denote hydrogen
atoms, or alkyl or phenylalkyl groups and R6 denotes a :
Cl5-alkyl, phenylalkyl or phenyl group),
or, if E denotes a straight-chain or branched Cl 5-
alkylene or C15-alkenylene group substituted by a
hydroxy, alkoxy, alkylsulphenyl, R3R4N-, R30-C0-, R6C0-
NR3-, R6o-co-NR3-~ R6S02-NR3- or R3R4N C0 NR5 gr p
(wherein R3, R4, Rs and R6 are as hereinbefore defined~,
then A may also denote a phenyl group substituted in the
4-position by a RaNH-CH2- or RaNH-C(=NH)- group, or a
phenyl group to which a C34-n-alkylene bridge
substituted by a RaNH group is attached via two adjacent
carbon atoms;
- 3 ~ 2 ~ 8
Ra denotes a hydrogen atom or an alkyl, phenylalkyl, (C
5-alkoxy)carbonyl, phenylalkoxycarbonyl, (C35-
alkenyl)oxycarbonyl, (C57-cycloalkyl)oxycarbonyl, or R1-
CO-O-(R2CH)-O-CO-group;
R1 denotes a C15-alkyl, C57-cycloalkyl, phenylalkyl, C15-
alkoxy, C57-cycloalkyloxy or phenyl group;
R2 denotes a hydrogen atom or a C14-alkyl, C57-cycloalkyl
or phenyl group;
B denotes a bond or an alkylene, -OCH2-, -CH20-,
-SCH2-, -CH2S-, -CONR~-, -R3NCO-, -CH2NR3-, -NR3CH2-,
-SO2NR3- or -NF~SO2- group, wherein F~ is as hereinbefore
defined and an oxygen or nitrogen atom of group B is not
directly bonded to a nitrogen atom of group A or to a
ring nitrogen of the five-membered heterocyclic ring;
C' denotes a phenylene group optionally mono- or
- disubstituted by fluorine, chlorine or bromine atoms or
by alkyl, trifluoromethyl, hydroxy, alkoxy,
alkylsulphenyl, alkylsulphinyl, or alkylsulphonyl
groups, wherein the substituents may be identical or
different,
or C' denotes a pyridenylene, pyrimidinylene,
pyrazinylene or pyridazinylene group, optionally
substituted in the carbon skeleton by a chlorine atom or
by an alkyl or alkoxy group,
or C' denotes a 1,4-cyclohexylene, 1,3-piperidinylene,
1,4-piperidinylene or 1,4-piperazinylene group,
or, if A is not a pyridyl group and B is an alkylene,
-CONH- or -CH2S- group, then C may also denote a bond,
and if A is an amidinophenyl group and B is a bond then
C may also denote a bond);
'.''`t '
2~i~178
-- 4
a second of the groups X1, X2, X3, X4 and X5 is a group of
formula
.'- ':-
RbO-CO - E - D - N< , ~ :
RbO-CO - E - D - CH< or
RbO-CO - E - D - C<
(wherein
D denotes a -C0-NR3-, -NF~-CO-, -S02-NR3 or -NR3-S02-
group, a straight-chain or branched C18-alkylene or
C28-alkenylene group optionally substituted by a
hydroxy, alkoxy, alkylsulphenyl, R3R4N-, R30-C0-, R6C0- :.
NR3-, R~0-C0-NR3-, R6S02-NR3- or R3R4N-C0-NR5- group, ~ :
wherein R3, R4, R5 and R6 are as hereinbefore defined,
or D denotes a phenylene group optionally mono- or
disubstituted by fluorine, chlorine, or bromine atoms or
by alkyl, trifluoromethyl, hydroxy, alkoxy,
alkylsulphenyl, alkylsulphinyl or alkylsulphonyl groups,
.
or D denotes a pyridenylene, pyrimidinylene,
pyrazinylene, pyridazinylene or triazinylene group ~.
optionally substituted in the carbon skeleton by a
chlorine atom or by an alkyl or alkoxy group, and in
which additionally one or two -CH=N- groups may each be
replaced by a -C0-NR3- group, wherein R3 is as
hereinbefore defined, and one of the nitrogen atoms,
instead of being bonded to the group R3, may also be
bonded to the group E (if this group is itself not a::
bond and is not bonded to the group D via an oxygen or
sulphur atom) or to the ring atom of the said second of
the groups X1, X2, X3, X4 and X5, . :
.....
or D denotes a C4s-cycloalkylene group optionally
substituted by an alkyl, phenylalkyl or phenyl group,
wherein a >CH-unit may be replaced by a nitrogen atom
and, additionally a methylene group adjacent to this
:,
2~4178
- 5
nitrogen atom may be replaced by a carbonyl group,
or D denotes a C67-cycloalkylene group optionally
substituted by an alkyl, phenylalkyl or phenyl group,
wherein one or two >CH-units may each be replaced by a
nitrogen atom, and, additionally, one or two methylene
groups adjacent to such a nitrogen atom may each be
replaced by a carbonyl group,
or D denotes a C15-alkylene group bonded via a group W1
to the ring atom of the said second of the groups X1, X2,
X3, X4 and Xs~ wherein W~ denotes a NR3-group (in which R3
is as hereinbefore defined) or an oxygen or sulphur
atom, whilst an oxygen or sulphur atom W1 cannot be
directly bound to a ring nitrogen atom of the five-
membered heterocyclic ring;
E, unless at the same time C' denotes a bond and A
denotes a l-methyl- or l-benzyl-4-piperazinyl group, may ~-
denote a bond,
or E denotes a straight-chain or branched C1s-alkylene
or C25-alkenylene group optionally substituted by a
hydroxy, alkoxy, alkylsulphenyl, R3R4N-, R30-CO-,
R6C-NR3-~ R60-C-NR3-, R6S02-NR3- or R3R4N CO NRs gr p
wherein R3, R4, Rs and R6 are as hereinbefore defined,
or E denotes an alkylene group bonded to group D via a
group W2, wherein W2 denotes an oxygen or sulphur atom or
a sulphinyl, sulphonyl, -NR3-, -(R6CO)N-, -(R6SO~)N-, ~
-CONR3- or NR3CO- group, wherein R3 and R6 are as ~.
hereinbefore defined and wherein an oxygen or sulphur
atom W2 is not directly bound to a nitrogen atom of group
D; and
Rb denotes a hydrogen atom, a C15-alkyl group, a C3 5-
alkenyl group, a phenyl(C13-alkyl) group, a Cs 7-
--` 21~178
- 6 -
cycloalkyl group, a (Cs7-cycloalkyl)alkyl group or a R1-
C0-0-(R2CH)-group, wherein R1 and R2 are as hereinbefore :~
defined, the separation between the furthest nitrogen
atom of group A and the COORb group being at least ll
bonds);
a third of the groups X1, X2, X3, X4 and Xs denotes a
sulphur atom, a HN<,R6N<, R7C< or (R7)2C< group or a
nitrogen atom, wherein R6 is as hereinbefore defined and
R7 denotes a hydrogen atom or an alkyl, phenylalkyl,
phenyl, alkoxy, R3R4N-, R30-C0- or R3R4N-C0- group,
wherein R3 and R4 are as hereinbefore defined;
a fourth of the groups X1, X2, X3, X4 and X5 denotes an
oxygen, sulphur or nitrogen atom or a R7CS group, wherein
R7 is as hereinbefore defined, or a carbonyl group if it
is not positioned between two ring nitrogen atoms; and
the fifth of the groups X1, X2, X3, X4 and X5 denotes a
nitrogen atom or a R7C< or (R7)2C< group, wherein R7 is as
hereinbefore defined;
or two adjacent X1, X2, X3, X4 and X5 groups may together
denote an o-phenylene group; and
wherein, unless otherwise specified, each alkyl,
alkylene or alkoxy moiety contains l to 3 carbon atoms)
or an isomer (eg. tautomer, stereoisomer or mixture
thereof) or a salt thereof.
Thus formula I includes for example substituted furan,
tetrahydrofuran, 2,3-dihydro-furan, 2,5-dihydro-furan, -~
thiophene, 2,3-dihydro-thiophene, 2,5-dihydro-thiophene,
tetrahydrothiophene, l,2-dithiolane, l,3-dithiolane,
pyrrole, indole, isoindole, 2,3-dihydro-indole, 2,3-
dihydro-isoindole, 2-indolone, imidazole, 4,5-dihydro- :;.
-~ ~
~ . .
21~4~7~
- 7
imidazole, tetrahydroimidazole, benzimidazoline,
pyrazole, 2H-pyrazol-5-one, 4,5-dihydro-pyrazole, 2,3-
dihydro-pyrazole, indazole, 2,3-dihydro-indazole,
oxazole, isoxazole, oxazoline, oxazolidine, thiazole,
isothiazole, thiazoline, thiazolidine, 1,3,4-oxadiazole,
l,3,4-thiadiazole, l,2,3-triazole, l,2,4-triazole and
tetrazole derivatives.
Preferred compounds according to the invention include
those of formula I wherein:
a first of the groups X~, X2, X3, X4 and Xs represents a
group of formula
A - B - C' - N< , :
A - B - C' - CH< or
A - B - C' - C<
(wherain
A denotes a pyridyl or quinuclidinyl group,
or a C57-cycloalkyl group optionally substituted by l to
4 alkyl groups or by a hydroxy, alkoxy, cyano, .
aminocarbonyl, carboxy or alkoxycarbonyl group, wherein
an unsubstituted ring methylene group is replaced by an
Ra-N< group,
and, additionally, in a 6- or 7-membered azacycloalkyl
group thus formed a >CH-unit in the 4-position is
optionally replaced by a nitrogen atom, or in a 5- to 7-
membered azacycloalkyl group thus formed a -CH2-CH<-unit
is optionally replaced by a -CH=C<-unit, ::
or if D is a C1s-alkylene group substituted by a R3R4N- :~
CO-NR5- or R6-S02-NR3- group (wherein R3, R4 and R5
independently denote hydrogen atoms or alkyl or
phenylalkyl groups and R6 denotes a Cl5-alkyl,
- 8 _ 211417~
phenylalkyl or phenyl group),
or if ~ is a straight-chain or branched C15-alkylene
group substituted by a R3R4N-, R6-CO-NR3-, R6-SO2-NR3, -
R3R4N-CO-NR5-, hydroxy or alkoxy group (wherein R3, R4, R5
and R6 are as hereinbefore defined),
then A may also denote a phenyl group substituted in the
4-position by a RaNH-CH2- or RaNH-C(=NH)- group, or a
phenyl group to which a n-propylene or n-butylene bridge
is attached via the positions 3 and 4, wherein the n-
propylene and n-butylene bridge is substituted by a RaNH-
group; :
Ra denotes a hydrogen atom or an alkyl, phenylalkyl, (C5-alkoxy)carbonyl, phenylalkoxycarbonyl, ( Cs 7-
cycloalkyl)oxycarbonyl or R1-CO-O-(R2CH)-O-CO- group;
R1 denotes an alkyl, Cs7-cycloalkyl, C15-alkoxy, . .
C57-cycloalkoxy or phenyl group; ~
R2 denotes a hydrogen atom or a C14-alkyl group: ;:
B denotes a bond or a -CH2-CH2-, -OCH2-, -CH20-, -CONR3-, :
or -R3NCO- group, wherein R3 is as hereinbefore defined
and an oxygen and nitrogen atom of group B is not
directly bonded to a nitrogen atom of group A or to a
ring nitrogen of the five-membered heterocyclic ring;
C' denotes a phenylene group optionally mono- or :~
disubstituted by fluorine, chlorine, or bromine atoms or
by alkyl, trifluoromethyl, hydroxy or alkoxy groups,
wherein the substituents may be identical or different,
or C' denotes a pyridinylene, pyrimidinylene,
pyrazinylene or pyridazinylene group optionally
substituted in the carbon skeleton by an alkyl or alkoxy
- 9 - 21~4~78
group,
or C' denotes a 1,4-cyclohexylene, 1,4-piperidinylene or
1,4-piperazinylene group,
or, if A does not denote a pyridyl group and B denotes
an ethylene or CONH- group, C' may also denote a bond,
or, if A is an amidinophenyl group and B denotes a bond
C' may also denote a bond);
a second of the groups X~, X2, X3, X4 and Xs is a group of
formula
RbO--CO - E -- D - N<,
RbO-CO - E - D - CH< or
RbO-CO - E -- D -- C<
(wherein D denotes a -CO-NR3- or -NR3-CO- group or a
straight-chain or branched C15-alkylene or C25alkenylene
group optionally substituted by a hydroxy, alkoxy,
R~R4N-, R6CO-NR3~, R6o-CO-NR3-~ R6S02-NR3~ or R3R4N-C-NR~-
group, wherein R3, R4, R5 and R6 are as hereinbefore .
defined,
or D denotes a phenylene group optionally mono- or
disubstituted by fluorine, chlorine or bromine or by
alkyl, trifluoromethyl, hydroxy or alkoxy groups,
or D denotes a pyridinylene, pyrimidinylene,
pyrazinylene or pyridazinylene group optionally
substituted in the carbon skeleton by an alkyl or alkoxy
group,
or D denotes a cyclohexylene group, wherein one or two
>CH-units are optionally replaced by a nitrogen atom and
additionally a methylene group adjacent to such a
nitrogen atom is optionally replaced by a carbonyl .
-
-- 10 --
group, 211~178
or D denotes a C14-alkylene group linked via a group W1
to the ring atom of said second of the groups X1~ X2~ X3,
X4 and Xs~ wherein W1 denotes an NR3-group (wherein R3 is
as hereinbefore defined) or an oxygen or sulphur atom, -
whilst an oxygen or sulphur atom W1 cannot be directly
linked to a ring nitrogen atom of the five-membered
heterocyclic ring;
E, unless C' denotes a bond and A denotes a 1-methyl or
l-benzyl-4-piperazinyl group, may denote a bond,
or E denotes a straight-chain or branched C15 alkylene
group optionally substituted by a hydroxy, alkoxy, : :.
R R N R co-NR -, R60-CO-NR3-~ R6SO2-NR3 or R3R4 5
group, wherein R3, R4, R5 and R6 are as hereinbefore -
defined,
or E denotes an alkylene group linked via a group W2 to
the group D, wherein W2 is an oxygen or sulphur atom or a
-~R3-, -(R6CO)N- or -(R6SO2)N- group (wherein R3 and R6 are
as hereinbefore defined) wherein an oxygen or sulphur -
atom W2 may not be directly linked to a nitrogen atom of
group D; and
Rb denotes a hydrogen atom or a C15-alkyl, phenyl-(C13-
alkyl), C57-cycloalkyl or R1-CO-O-(R2CH)-group, wherein R
and R2 are as hereinbefore defined, the separation
between the furthest nitrogen atom of group A and the
COORb-group being at least 11 bonds);
a third of the groups X1, X2, X3, X4 and X5 denotes a HN<, ~:
R6N<, R7CS or (R7)2C< group or an nitrogen atom, wherein
R6 is defined as above and R7 denotes a hydrogen atom or
an alkyl or phenyl group;
11- 2~1417~
a fourth of the groups X1~ X2, X3, X4 and X5 denotes an
oxygen, sulphur or nitrogen atom or a R7C< group, wherein
R7 is as hereinbefore defined; and
the fifth of the groups X1, X2, X3, X4 and Xs denotes a
nitrogen atom or a R7C< or (R7)2C< group, wherein R7 is as
hereinbefore defined;
or two adjacent Xl, X2, X3, X4 and Xs groups may together
denote an o-phenylene group)
or an isomer (eg. tautomer, stereoisomer, or mixture
thereof) or salt thereof.
More particularly preferred compounds according to the
invention include those of formula I wherein~
a first of the groups Xl, X2, X3, X4 and Xs is a group of
formula
A - B - C' - N< or
A - B - C' - CS
(wherein A denotes a 1,3-pyrrolidinyl, 1,3-piperidyl or
1,4-piperidyl group optionally substituted in the carbon
skeleton by l to 4 methyl groups or by a hydroxy,
methoxy, cyano or aminocarbonyl group, and wherein the
above-mentioned pyrrolidinyl and piperidyl groups are
substituted in the l-position by a group Ra (wherein Ra
denotes a hydrogen atom or a methyl, ethyl, benzyl, or
(C15-alkoxy)carbonyl group),
or A ~enotes a pyridyl or quinuclidinyl group, a 1,4-
piperazinyl or 3,4-dehydro-1,4-piperidyl group
substituted in the l-position by a group Ra (wherein Ra
is as hereinbefore defined),
;, ~, , , ~' . ~,
- 12 - 21~4178
or, if D denotes an ethylene group substituted by a R6-
SO2-NR3-group (wherein R3 denotes a hydrogen atom or a
methyl or ethyl group and R6 denotes a C15-alkyl group or
a phenyl group), .:
or, if E denotes an ethylene group substituted by an
amino, R6CO-NR3-, R6SO2-NR3- or hydroxy group (wherein R3
and R6 are as hereinbefore defined),
then A may also denote a phenyl group substituted in the
4-position by a RaNH-C (=NH) -group;
B denotes a bond or a -CH2-CH2-, -OCH2-, -CH20-, -CONCR3-
-R3NCO-group, wherein R3 is as hereinbefore defined and
an oxygen or nitrogen atom of group B is not directly
linked to a nitrogen atom of group A or of the five-
membered heterocyclic ring;
C' denotes a phenylene group optionally substituted by a
chlorine atom or by a methyl group,
or C' denotes a pyridinylene, pyrimidinylene,
pyridazinylene or 1,4-piperidinylene group, ::
or, if A is not a pyridyl group and B is an ethylene or -~
CONH-group, C' may also denote a bond,
or, if A is an amidinophenyl group and B is a bond C'
may also denote a bond);
a second of the groups X1, X2, X3, X4 and X5 denotes a
group of formula
RbO-CO ~ E ~ D ~ N< or
RbO-CO ~ E ~ D ~ C<
(wherein
- 13 - 21 t 417 8
D denotes a -CO-NR3- or -NR3-CO-group (wherein R3 is as
hereinbefore defined), or a straight-chain or branched
C15-alkylene group, .
or D denotes an ethylene group substituted by a R6SO2-
NR3- group,
or D denotes a phenylene group optionally substituted by
a chlorine atom or a methyl group,
or D denotes a 1,4-cyclohexylene group,
or D denotes a C14-alkylene group linked to the ring
atom of said second of the groups X1, X2, X3, X~, and X5
via a -NR3-group (wherein R3 is as hereinbefore defined);
E, unless C' denotes a bond and A denotes a 1-methyl or
1-benzyl-4-piperazinyl group, may denote a bond,
or E denotes an ethylene group optionally substituted by
a R6CO-NR3- or R6SO2-NR3- group (wherein R3 and R6 are as
hereinbefore defined);
or E denotes a -O-CH2- or -NR3-CH2- group (wherein R3 is
as hereinbefore defined); and
Rb denotes a hydrogen-atom or a C15-alkyl, or C56- :
cycloalkyl group, the separation between the furthest
nitrogen atom of group A and the COORb-group being at
least 11 bonds); ~
a third of the groups X1, X2, X3, X4 and X5 denotes a HN<, ~:
R6N< or R7C< group or a nitrogen atom (wherein R6 is as
hereinbefore defined and R7 is a hydrogen atom or a
methyl or ethyl group);
a fourth of the groups X1, X2, X3, X4 and X5 denotes an
.. . ::
': '~ ' .
21~ ~178
- 14 -
oxygen, sulphur or nitrogen atom or a R7C< group (wherein
R7 is as hereinbefore defined); and
the fifth of the groups X1, X2, X3, X4 and Xs denotes a
nitrogen atom or a R7CS group (wherein R7 is as
hereinbefore defined);
or two adjacent X1, X2, X3, X4 and Xs groups together
denote an o-phenylene group;
and the isomers (eg. tautomers, stereoisomers, including
mixtures thereof) and the salts thereof.
More particularly preferred compounds according to the
invention include those of formula I wherein: ~ .
a first of the groups X1, X2, X3, X4 and X5 denotes a
group of formula
A - B - C' - N< or ~.
A - B - C' - CS
(wherein
A denotes a 4-piperidyl group substituted in the 1-
position by a group Ra (wherein Ra denotes a hydrogen
atom or a benzyl or C15-alkoxycarbonyl group),
.
or A denotes a 1,4-piperazinyl group substituted in the
1-position by a group Ra (wherein Ra is as hereinbefore
defined),
or, if D is an ethylene group substituted by a R6-SO2-
NR3-group (wherein R3 is a hydrogen atom and R~ is an Cls-
alkyl group), A may also denote a phenyl group
substituted in the 4-position by a NH2-C(=NH)- group;
B denotes a bond or a -CH2-CH2- or -CH20- group;
i
21~4178
- 15 -
c' denotes a phenylene or a 1,4-piperidinylene group or,
if B is not also a bond, C' may also denote a bond);
a second of the groups X1 ~ X2, X3, X4 and Xs denotes a
group of formula
:
RbO--CO-E--D-C<
(wherein
D denotes a -CO-NH-, C15-alkylene, phenylene or 1,4-
cyclohexylene group or an ethylene group substituted by
a R6-SO2-NR3-group (wherein R6 is as hereinbefore
defined);
E, unless C' denotes a bond and A denotes a 1-benzyl-4-
piperazinyl group, may denote a bond,
or E denotes an ethylene group, and
Rb denotes a hydrogen atom or a C14-alkyl group, the
separation between the furthest nitrogen atom and the : :
COORb-group being at least 11 bonds);
a third of the groups X1, X2, X3, X4 and X5 denotes a
phenyl-N< or R7C< group or a nitrogen atom (wherein R7 is
a hydrogen atom or a methyl or ethyl group); ;~
a fourth of the groups X1, X2, X3, X4 and X5 denotes an
oxygen, sulphur or nitrogen atom or a R7C< group (wherein
R7 is as hereinbefore defined); and
the fifth of the groups X1, X2, X3, X4 and X5 denotes a - --
nitrogen atom; ~-~
and the isomers (eg. tautomers, stereoisomers including
mixtures thereof) and salts thereof.
2 ~ 8
- 16 -
Particularly preferred compounds according to the: :
invention include:
(i) 2-(trans-4-carboxycyclohexyl)-5-[4-(4-piperidyl)- ~`
phenyl]-l,3,4-thiadiazole,
(ii) 2-~trans-4-(methoxycarbonyl)-cyclohexyl]-5-[4-(4-
piperidyl)-phenyl]-1,3,4-thiadiazole,
(iii) 1-[6-(4-amidinophenyl)-3-pyridazinyl]-4-[2-~n-
butanesulphonylamino)-2-carboxy-ethyl]-imidazole, : :
(iv) 1-[6-(4-amidinophenyl)-3-pyridazinyl]-4-[2-(n-
butanesulphonylamino)-2-(methoxycarbonyl)-ethyl~- :
imidazole,
:
(v) 2-[trans-4-(isobutyloxycarbonyl)-cyclohexyl]-5-[4-
(4-piperidinyl)-phenyl]-1,3,4-thiadiazole and
(vi) 2-[trans-4-(ethyloxycarbonyl)-cyclohexyl]-5-[4-(4-
piperidinyl)-phenyl]-1,3,4-thiadiazole
and the salts thereof.
Viewed from a different aspect the invention provides a
process for preparing a compound of formula I or salt
thereof, said process comprising at least one of the
following steps:
a) (to prepare a compound of formula I, wherein the
second of the groups X1~ X2 ~ X3 ~ X4 and X5 is a RbO-CO-E-D-
CH< or RbO-CO-E-D-C< group)
reacting a compound of formula II
17 2~4~8
- .: .
X1 ~ ~:
X ' `X (Il) ~
X3-X4 . ~.
(wherein X1, X2, X3, X4 and X5 are as hereinbefore defined
with the proviso that a second of the groups X1, Xz, X3,
X4 and Xs denotes an HO-CO-CH< or HO-CO-C< group) or a
reactive derivative thereof
with a compound of formula III
..: '~` :' , '
RbO - CO - E - HNR3 (III) -~-~
(wherein
R3, Rb and E are as hereinbefore defined); ~ ;
b) (to prepare compounds of formula I, wherein Ra
denotes a hydrogen atom)
:, ~:' .
cleaving a protecting group from a compound of formula
IV ~-
X .~.
`X5 (
X3-X4
(wherein X1, Xz, X3, X4 and X5 are as hereinbefore defined :
with the proviso that Ra denotes a (C15-alkoxy)carbonyl,
phenylalkoxycarbonyl, (C35-alkenyloxy)carbonyl, (C57~
cycloalkyl)oxycarbonyl group or a cleavable imino group
protecting group such as an acetyl, trifluroacetyl,
benzoyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl
- 18 - 2 ~ ~17
group)
: '
by hydrolysis, hydrogenolysis or thermolysis;
c) (to prepare compounds of formula I, in which Rb
denotes a hydrogen atom)
cleaving a protecting group from a compound of formula V
X2' `Xs
x3-x4
(wherein Xl, X2, X3, X4 and X5 are as hereinbefore defined
with the proviso that Rb denotes a C15-alkyl, C3 5-
alkenyl, phenyl(Cl3-alkyl), C57-cycloalkyl or (C5 7-
cycloalkyl)alkyl group or a cleavable carboxy group
protecting group such as a trimethylsilyl,
methoxybenzyl, or 2,4-dimethoxybenzyl or
tetrahydropyranyl group)
by hydrolysis, hydrogenolysis or thermolysis;
d) (to prepare 1,3,4-oxadiazole, 1,2,4-triazole and
1,3,4-thiadiazole compounds of formula I)
cyclising a compound of formula VI
N--N
R' C C--R"
Z~ Z2
2 ~ r~
-- 19 --
(wherein Z1 and Z2 independently denote halogen atoms,
amino groups optionally substituted by a group R6, or
hydroxy, alkoxy, mercapto or alkylmercapto groups,
and one of the groups R' or R~ denotes an A-B-C'- group
and the other denotes a RbO-CO-E-D- group)
which may optionally be formed in the reaction mixture
and if necessary subsequently alkylating the product
formed;
,
e) (to prepare compounds of general formula I, in
which A denotes a phenyl group substituted in the 4-
position by a RaNH-C (=NH) - group) ~ -
. . .
reacting a compound of formula VII
X2- X5 ~ll)
X3-X4 ~ ~
~ .
(wherein X1, X2~ X3, X4 and X5 are as hereinbefore defined -
with the proviso that A denotes a phenyl group ~-
substituted in the 4-position by a Z3-C (=NH)- group
(wherein Z3 denotes an alkoxy or aralkoxy group such as a
methoxy, ethoxy, n-propoxy, isopropoxy or benzyloxy
group, or an alkylthio or aralkylthio group such as
methylthio, ethylthio, n-propylthio or benzylthio group,
or an amino group)), which may optionally be formed in ~:~
the reaction mixture,
with an amine of formula VIII
Ra~ - NH2 (VIII)
.
:~ '
21~417~
- 20 -
(wherein Ra' denotes a hydrogen atom or a C13-alkyl
group~;
f) (to prepare compounds of general formula I, wherein
A denotes a phenyl group substituted in the 4-position
by a R~NH-C(=NH)-group)
reacting a compound of formula IX
X / `X (IX)
x3-x4
(wherein X1, X2, X3, X4 and X5 are as hereinbefore defined
with the proviso that A denotes a phenyl group
substituted in the 4-position by a cyano group)
with hydroxylamine and subsequently reducing the
resultant amidoxime;
g) (to prepare compounds of formula I, wherein A is a
phenyl group substituted in the 4-position by a RaNH-
C(=NH)- group)
reacting a compound of formula IX
X2' `X (IX)
X3-X4
(wherein X1, X2, X3, X4 and Xs are as hereinbefore defined
with the proviso that A denotes a phenyl group :
substituted in the 4-position by a cyano group) ~ .
~. ~ . . : I
~1~4178
- 21 -
with an alkylchloroaluminiumamide; - .
h) (to prepare 1,3-thiazolenes and imidazolenes of .
formula I)
reacting a compound of formula X
R~ - CO - CH2 - Z4 (X)
with a compound of formula XI
R" - CU - NH2 (XI)
(wherein one of the groups R ~ and R" denotes an A-B-C' : ~ :
group and the other denotes a RbO-CO-E-D- group,
Z4 denotes a nucleophilic leaving group, such as a ~ :
chlorine, bromine, or iodine atom,
.
and U denotes a sulphur atom or an imino group)
i) (to prepare compounds of formula I, wherein Ra is as
hereinbefore defined with the exception of the hydrogen
atom, and B denotes a -CH20- group)
reacting a compound of formula XII
A - CH2 - Z5 (XII)
~,
(wherein A is as hereinbefore defined with the proviso .
that Ra is as hereinbefore defined with the exception of
the hydrogen atom, and Zs denotes a nucleophilic leaving .
group such as a halogen atom or a sulphonyloxy group, ~ :
for example a methanesulphonyloxy group or a chlorine or :
bromine atom) -
with a compound of formula XIII
21~78
- 22 -
x1\
x2~ x5 (X1113
x3-x4
(wherein Xll X2~ X3~ X4 and X5 are as hereinbefore defined
with the proviso that one of X1 ~ X2, X3, X4 and X5 denotes
a HO-C'-CH< or HO-C'-C< group, wherein C' is as
hereinbefore defined) or an alkali or alkaline earth
metal salt such as a lithium, sodium, potassium, cesium,
magnesium, or calcium salt thereof;
j) (to prepare compounds of formula I, wherein one of
the groups X1~ X2, X3, X4 and X5 denotes an A-B-C ' -N< or
RbO-CO-E-D-N< group)
alkylating a compound of formula XIV
X / 1`X (Xl\/)
X3-X4
(wherein X1, X2, X3, X4 and Xs are as hereinbefore defined -~
with the proviso that one of X1, X2, X3, X4 and X5 denotes
an imino group)
with a compound of formula XV
.
W - Z6 (XV)
(wherein W denotes an A-B-C ' - or RbO-CO-E-D- group,
wherein A, B, C' and D are as defined above, and Z6
denotes a nucleophilic leaving group, e.g. a halogen
atom or a sulphonyloxy group such as a
.~,. . . ~ ~ ..
21~417~
- 23 -
methanesulphonyloxy group or a chlorine or bromine
atom);
k) (to prepare compounds of formula I, wherein Rb
denotes a R1-CO-O-(R2CH)-group (in which R1 and R2 are as
hereinbefore defined), a C15-alkyl groupl a C3s-alkenyl
group, a phenyl-(C13-alkyl) group, a C57-cycloalkyl group
or a (C57-cycloalkyl)alkyl group)
esterifying a compound of formula XVI
X2' X5 ~ 1) ~.
3 4
(wherein Xl, X2, X3, X4 and Xs are defined as above with
the proviso that Rb denotes a hydrogen atom)
with a compound of formula XVII
z7 _ Rb~ (XVII)
(wherein Rb' denotes a R1-CO-O-(R2CH)- group (in which R1
and R2 are as hereinbefore defined), a C1s-alkyl group, a
C35-alkenyl group, a phenyl(C13-alkyl) group, a C5 7-
cycloalkyl group or a (Cs7-cycloalkyl)alkyl group, and
27 denotes a hydroxy group or a nucleophilic leaving
group such as a halogen atom or a sulphonyloxy group,
e.g. a chlorine, bromine or iodine atom or a : :
methanesulphonyloxy or p-toluenesulphonyloxy group);
l) performing any one of steps (a) to (k) using a
protected reagent and subsequently removing the
protecting groups from the product;
- 24 - 2114~78
m) converting a compound of formula I into a salt
thereof; and
n) resolving a compound of formula I into its isomers.
The reaction of step (a) is expediently carried out in a
solvent or solvent mixture such as methylene chloride,
dimethylformamide, dimethylsulphoxide, benzene, toluene,
chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran
or dioxane, optionally in the presence of a dehydrating
agent, for example in the presence of isobutyl
chloroformate, thionyl chloride, trimethylchlorosilane,
hydrochloric acid, sulphuric acid, methanesulphonic
acid, p-toluenesulphonic acid, phosphorus trichloride,
phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide,
N,N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide, 2-
t(lH)-benzotriazolyl]-1,1,3,3-tetramethyl-uronium-salts,
N'N'-thionyldiimidazole, N,N'-carbonydiimidazole or
triphenylphosphine/carbon tetrachloride, optionally in
the presence of dimethylaminopyridine or 1-hydroxy-
benzotriazole and/or a base such as triethylamine, N-
ethyl-diisopropylamine or N-methyl-morpholine, suitably
at temperatures between -10 and 150C, preferably at
temperature between 0 and 50C.
The hydrolysis of step (b) is appropriately carried out
either in the presence of an acid such as hydrochloric
acid, hydrobromic acid, sulphuric acid, phosphoric acid,
acetic acid, acetic acid/hydrochloric acid,
trichloroacetic acid or trifluoroacetic acid, or in the
presence of a base such as lithium hydroxide, sodium
hydroxide or potassium hydroxide, in a suitable solvent
such as water, methanol, water/methanol, ethanol,
water/ethanol, water/isopropanol, water/tetrahydrofuran,
ether/dioxane or water/dioxane, at temperatures between
-lO~C and 120C, e.g. at temperatures between ambient
temperature and the boiling temperature of the reaction
- 25 - 21~178
mixture.
In the acid hydrolysis, depending on the conditions
used, other hydrolytically cleavable groups such as
alkoxycarbonyl or phenylalkoxycarbonyl groups optionally
present in a compound of formula IV, may also be cleaved
simultaneously.
When Ra denotes, for example, a tert.butyloxycarbonyl
group, the tert.butyl group may also be cleaved by
treating with an acid such as trifluoroacetic acid,
hydrochloric acid, formic acid, p-toluenesulphonic acid,
sulphuric acid, phosphoric acid or polyphosphoric acid,
optionally in an inert solvent such as methanol,
methylene chloride, chloroform, benzene, toluene,
tetrahyrofuran, dioxane, ether/dioxane, or -~ ~-
ether/dioxane/methanol preferably at temperatures
between -10C and 120C, e.g. at temperatures between 0
and 60C, or optionally thermally in an inert solvent
such as methylene chloride, chloroform, benzene,
toluene, tetrahydrofuran or dioxane and optionally in
the presence of a catalytic amount of an acid such as p-
toluenesulphonic acid, sulphuric acid, phosphoric acid,
or polyphosphoric acid, preferably at the boiling
temperature of the solvent used, e.g. at temperatures
between 40C and 100C.
,
When Ra represents, for example, a benzyloxycarbonyl
group, the benzyl group may also be hydrogenolytically
cleaved in the presence of a hydrogenation catalyst such
as palladium/charcoal, in a suitable solvent such as
methanol, ethanol, ethanol/water, glacial acetic acid, -
ethyl acetate, dioxane or dimethylformamide, preferably
at temperatures between 0 and 50 D C, e.g. at ambient
temperature, under a hydrogen pressure of 1 to 10 bar.
During the hydrogenolysis, other groups may
simultaneously be reduced, e.g. a nitro group may to a
:
21~4178
- 26 -
amino group or a benzyloxy group to a hydroxy group, or
a benzylamino group to an amino group. Furthermore, any
C=C double bonds may simultaneously be hydrogenated to
single bonds.
The hydrolysis of step (c) is appropriately carried out
either in the presence of an acid such as hydrochloric,
sulphuric acid, phosphoric acid, acetic acid,
acetic/hydrochloric acid, trichloroacetic acid or
trifluoroacetic acid, or in the presence of a base such
as lithium hydroxide, sodium hydroxide or potassium
hydroxide, in a suitable solvent such as water,
methanol, water/methanol, ethanol, water/ethanol,
water/isopropanol, water/tetrahydrofuran or
water/dioxane, at temperatures between -10C and 120C
e.g. at temperatures between ambient temperature and the
boiling temperature of the reaction mixture.
In the acid hydrolysis, depending on the conditions
used, other hydrolytically cleavable groups such as
acetyl, trifluoroacetyl, benzoyl, tert.butyloxycarbonyl
or benzyloxycarbonyl group optionally present in a
compound of formula V may simultaneously be cleaved.
:
When Rb denotes, for example, a tert.butyl group, this ~ ~
may also be cleaved by treating with an acid such as -
trifluoroacetic acid, hydrochloric acid, formic acid, p-
toluenesulphonic acid, sulphuric acid, phosphoric acid
or polyphosphoric acid, optionally in an inert solvent
such as methylene chloride, chloroform, benzene,
toluene, tetrahydrofuran or dioxane, preferably at
temperatures between -10C and 120C, e.g. at
temperatures between 0 and 60~C, or thermally,
optionally in an inert solvent such as methylene
chloride, chloroform, benzene, toluene, tetrahydrofuran
or dioxane and optionally in the presence of a catalytic
amount of an acid such as p-toluenesulphonic acid,
.
.~ .
21~178
- 27 -
sulphuric acid, phosphoric acid, or polyphosphoric acid,
preferably at the boiling temperature of the solvent
used, e.g. at temperatures between 400C and 100C.
When Rb represents, for example, a benzyl group, the
benzyl group may also be hydrogenolytically cleaved in
the presence of a hydrogenation catalyst such as
palladium/charcoal, in a suitable solvent such as
methanol, ethanol, ethanol/water, glacial acetic acid,
ethyl acetate, dioxane or dimethylformamide, preferably
at temperatures between 0 and 50C, e.g. at ambient
temperature, under a hydrogen pressure of 1 to 10 bar.
During the hydrogenolysis, other groups may
simultaneously be reduced, e.g. a nitro group to an
amino group or a benzyloxy group to a hydroxy group, and
a benzylamino or benzyloxycarbonylamino group to an
amino group. At the same time, C=C-double bonds may,
moreover, be hydrogenated to single bonds.
The reaction of step (d) is expediently carried out in
solvent such as tetrahydrofuran, dioxane, 1,2-
dichlorobenzene or pyridine, at temperatures up to the
boiling temperature of the solvent used e.g. at
temperatures at between 20 and 180C.
When, in a compound of general formula VI, Z1 and Zz each
represent a hydroxy group, to prepare a 1,3,4-oxadiazole
derivative the reaction is preferably carried out in the
presence of a desiccating substance such as thionyl
chloride, and
to prepare a 1,3,4-thiadiazole derivative the reaction
is preferably carried out in the presence of a sulphur-
introducing reagent such as 2,4-bis(4-methoxyphenyl)-
1,3-dithia-2,4-diphosphetane-2,4-disulphide and
.
to prepare a 1,3,4-triazole derivative the reaction is
- 28 - 2~178
preferably carried out in the presence of a halogen-
introducing reagent such as phosphorus trichloride and
in the presence of aniline.
In order to prepare the other l,2,4-triazole
derivatives, a compound of general formula VI, in which -
one of the groups Z1 and Z2 is a hydroxy group and the --
other of the groups Z1 and Z2 is an amino group, is
cyclised and then alkylated if necessary.
The subsequent alkylation is suitably carried out in a
solvent such as methylene chloride, tetrahydrofuran,
dioxane, dimethylsulphoxide or dimethylformamide
optionally in the presence of a base such as sodium
carbonate, potassium carbonate or sodium hydroxide
solution or in the presence of a tertiary organic base
such as N-ethyl-diisopropylamine or N-methyl-morpholine
which may simultaneously serve as solvent, at
temperatures between -30 and 100C, but preferably at
temperatures between -lO and 80C.
The reaction of step (e) is appropriately carried out in `~
a solvent such as methanol, ethanol, n-propanol, water,
methanol/water, tetrahydrofuran or dioxane at
temperatures between 0 and 150C, preferably at
temperatures between 20 and 120C with a correspondingly
free amine or with a corresponding acid addition salt -
such as e.g. ammonia carbonate or ammonia acetate.
A compound of general formula VII is obtained, for
example, by reacting a corresponding nitrile with a
corresponding alcohol such as methanol, ethanol,
propanol, isopropanol or benzylalcohol, in the presence
of an acid such as hydrochloric acid or in the presence
of a corresponding alcoholate such as sodium methoxide,
or sodium ethoxide, or by reacting a corresponding amide
with a trialkyloxonium salt such as triethyloxonium-
~ ~, Z
- 29 - 211~78
tetrafluoroborate, in a solvent such as methylene
chloride, tetrahydrofuran or dioxane, at temperatures
between -10 and 50C but preferably at temperatures
between 0 and 20OC, or by reacting a corresponding
nitrile with hydrogen sulphide, suitably in a solvent
such as pyridine or dimethylformamide and in the
presence of a base such as triethylamine, and subsequent
alkylation of the resultant thioamide with a
corresponding alkyl or aralkyl halide.
The reaction of step (f) with hydroxylamine is
appropriately carried out in a solvent such as methanol,
ethanol, n-propanol, water, methanol/water,
ethanol/water, tetrahydrofuran or dioxane, optionally
with the addition of a base such as e.g. sodium
carbonate, at temperatures between 0 and 100C, bùt
preferably at temperatures between 20 and 80C, either
with free hydroxylamine or with a corresponding acid
addition salt such as the hydrochloride.
The subsequent reduction is preferably carried out in a
suitable solvent such as methanol, methanol/water, ~ -
methanol/ammonia, methan~l/water/ammonia,
methanol/hydrochloric acid, ethanol, ether,
tetrahydrofuran, dioxane, dimethylformamide or glacial -~
acetic acid, in the presence of catalytically activated
hydrogen e.g. hydrogen in the presence of Raney-nickel, -~
platinum or palladium/charcoal at temperatures of
between 0 and 100C, preferably at temperatures between
20 and 80C.
The reaction of step (g), using an appropriate
corresponding alkylchloroaluminiumamide is preferably
carried out in a suitable solvent, such as benzene or
toluene, at temperatures of between 0 and 100C, but
preferably at a temperature between 20 and 80C, and the
resultant aluminium complex is then decomposed by
211L~7 8
- 30 -
hydrolysis, preferably using a suspension of silica gel
in chloroform (see R.S. Garigipati, Tetrahedron Letters
31, 1969 (1990)).
The reaction of step (h) is suitably carried out in a
solvent such as methanol, ethanol or isopropanol,
optionally in the presence of a base such as sodium
carbonate, at elevated temperatures e.g. at the boiling
temperature of the solvent used.
The reaction of step (i) is suitably carried out in a
solvent such as tetrahydrofuran, acetone, dioxane,
dimethylsulphoxide, sulpholane, dimethylformamide or
dimethylacetamide, in the presence of an inorganic base
such as potassium carbonate, cesium carbonate, sodium
hydroxide, potassium hydroxide, sodium hydride or
potassium tert.butoxide, or in the presence of tertiary
organic bases such as N-ethyl-diisopropylamine, which
may optionally, also serve as solvent, and optionally in
the presence of a phase transfer catalyst such as
polyethyleneglycol-750-monomethylether on polystyrene or
hexadecyl-trimethylammonium chloride, at temperatures
between 0 and 180C, but preferably at temperatures
between 10 and 160C.
:
The alkylation of step (j) is appropriately carried out
in a solvent or mixture of solvents such as
methylenechloride, dimethylformamide,
dimethylsulphoxide, benzene, chlorobenzene,
tetrahydrofuran, benzene/tetrahydrofuran or dioxane, in
the presence of an acid-binding agent, e.g. an
alcoholate such as potassium-tert.butoxide, or an
alkali/metal hydroxide such as sodium or potassium -~
hydroxide, or an alkali metal carbonate such as
potassium carbonate, or an alkali metal amide such as
sodium amide, or an alkali metal hydride such as sodium
hydride, suitably at temperatures between 0 and 150C,
211~17~
- 31 -
preferably at temperatures between 0 and 50C.
The esterification of step (k) is appropriately carried
out in a suitable solvent, for example in a
corresponding alcohol such as methanol, ethanol or
isopropanol, methylene chloride, tetrahydrofuran,
dioxane, pyridine, toluene or dimethylsulphoxide, in the
presence of an acid activating and/or dehydrating agent
such as hydrogen chloride, concentrated sulphuric acid,
thionyl chloride, ethyl chloroformate,
carbonyldiimadazole or N,N'-dicyclohexyl-carbodiimide or
the isourea esters thereof, optionally in the presence
of a reaction accelerator such as copper chloride, by
esterification, for example, with a corresponding
diester, or by reaction with a corresponding halogenide, .
- preferably in the presence of a base such as potassium :
carbonate, and optionally in the presence a reaction
accelerator such as potassium iodide, at temperatures --:
between 0 and 100C, but preferably at temperatures ::
between 20C and the boiling temperature of the solvent.
When Z7 denotes a nucleophilic leaving group, the
reaction is preferably carried out with an alkali metal
salt of a compound of formula XVI.
In the above reactions, the active groups optionally .
present such as hydroxy, carboxy, amino, alkylamino or
imino groups may be protected during the reaction by ~:
conventional protecting groups which may be cleaved
after the reaction.
For example, the hydroxy group protecting group may be a
trimethylsilyl, acetyl, benzoyl, tert.butyl, trityl,
benzyl or tetrahydropyranyl group, the carboxyl group,
protecting group may be a trimethylsilyl, methyl, ethyl,
tert.butyl, benzyl or tetrahydropyranyl group, and the
amino, alkylamino or imino group protecting group may be
2114178
- 32 -
an acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl,
tert.butoxycarbonyl, benzyloxycarbonyl, benzyl,
methoxybenzyl or 2,4-dimethoxybenzyl group and for the
amino group a phthalyl group may also be considered.
The optionally subsequent cleaving of a protecting group
may, for example, be carried out hydrolytically in an
aqueous solvent, e.g. in water, isopropanol/water,
tetrahydrofuran/water or dioxane/water, in the presence -~
of an acid such as trifluoroacetic acid, hydrochloric
acid or sulphuric acid or in the presence of an alkali
metal base such as lithium hydroxide, sodium hydroxide
or potassium hydroxide, or by ether cleaving, e.g. in
the presence of iodotrimethylsilane, at temperatures
between 0 and 100C, preferably at temperatures between
10 and 50C.
However, a benzyl, methoxybenzyl or benzyloxycarbonyl
group may for example be cleaved hydrogenolytically, eg.
using hydrogen in the presence of a catalyst such as -
palladium/charcoal, in a solvent such as methanol,
ethanol, ethyl acetate, dimethylformamide,
dimethylformamide/acetone or glacial acetic acid,
optionally with the addition of an acid such as
hydrochloric acid, at temperatures between 0 and 50C,
but preferably at ambient temperature, under a hydrogen
pressure of 1 to 7 bar, preferably 3 to 5 bar.
A methoxybenzyl group may also be cleaved in the
presence of an oxidising agent such as cerium(IV)-
ammonium nitrate, in a solvent such as methylene
chloride, acetonitrile or acetonitrile/water at ;
temperatures between 0 and 50C, but preferably at `
ambient temperature.
A 2,4-dimethoxybenzyl group, however, is preferably -
cleaved in trifluoroacetic acid in the presence of
21~417~
- 33 -
anisole.
A tert.butyl or tert.butyloxycarbonyl group is
preferably cleaved by treating with an acid such as
trifluoroacetic acid or hydrochloric acid, optionally
using a solvent such as methylene chloride, dioxane or
ether.
The cleaving of a phthalyl group is preferably carried
out in the presence of hydrazine or a primary amine such
as methylamine, ethylamine or n-butylamine in a solvent
such as methanol, ethanol, isopropanol, toluene/water or
dioxane at temperatures between 20 and 50c.
An allyloxycarbonyl group is cleaved by treating with a
catalytic amount of tetrakis-(triphenylphosphine)-
palladium(0), preferably in a solvent such as
tetrahydrofuran and preferably in the presence of an
excess of a base such as morpholine or 1,3-dimedone, at
temperatures between 0 and 100C, preferably at ambient
temperature and under inert gas, or by treating with a
catalytic amount of tris-(triphenylphosphine)-
rhodium(I)chloride in a solvent such as aqueous ethanol
and optionally in the presence of a base such as 1,4-
diazabicyclo[2.2.2~octane at temperatures between 20 and
70C.
.
Furthermore, the compounds of formula I obtained may be
resolved into their enantiomers and/or diastereomers as
mentioned hereinbefore. Thus, for example, cis/trans
mixtures may be resolved into their cis and trans
isomers, and chiral compounds may be resolved into their
enantiomers.
Thus, for example, the cis/trans mixtures obtained may
be resolved by chromatography into the cis and trans
isomers thereof and the compounds of formula I which
21~4~8
- 34 -
occur in racemate fo~m may be separated by methods known
~er se (see Allinger N. L. and Eliel E. L. in "Topics in
Stereochemistry", Vol. 6, Wiley Interscience, 1971) into
their optical antipodes and compounds of formula I
having at least 2 stereogPnic centres may be separated
on the basis of their physical-chemical differences
using known methods, e.g. by chromatography and/or
fractional crystallisation, into the diastereomers
thereof which, if they occur in racemic form, may
subsequently be separated into the enantiomers as
mentioned above.
~he separation of enantiomers is preferably effected by
column separation on chiral phases or by
recrystallisation from an optically active solvent or by
reacting with an optically active substance (especially
an acid or an activated derivative thereof or an
alcohol) which forms salts or derivatives such as esters -~
or amides with the racemic compound, and separating the
diastereomeric salt mixtures or derivative thus
obtained, e.g. on the basis of their different
solubilities, whilst the free antipodes may be released
from the pure diastereomeric salts or derivatives by the
action of suitable agents. Particularly common,
optically active acids include, for example, the D- and
L-forms of tartaric acid and dibenzoyltartaric acid, di-
o-tolyl tartaric acid, malic acid, mandelic acid,
camphorsulphonic acid, glutamic acid, aspartic acid or
quinic acid. Examples of optically active alcohols
include for example (+)- or (-)-menthol and examples of
optically active acyl groups in amides include for
example (+)- or (-)-menthyloxycarbonyl.
Moreover, the compounds of formula I obtained may be
converted into the salts thereof, particularly for
pharmaceutical use into the physiologically acceptable
salts thereof with inorganic or organic acids. Examples -
- 35 - 21~7~
of suitable acids include hydrochloric acid, hydrobromic
acid, sulphuric acid, phosphoric acid, acetic acid,
fumaric acid, succinic acid, lactic acid, citric acid,
tartaric acid or maleic acid.
In addition, the new compounds of formula I thus
obtained, if they contain a carboxyl group, may
subsequently, if desired, be converted into the addition
salts thereof with inorganic or organic bases, more
particularly, for pharmaceutical use, into the
physiologically acceptable addition salts thereof.
Examples of suitable bases include sodium hydroxide,
potassium hydroxide, ammonia, cyclohexylamine,
ethanolamine, diethanolamine and triethanolamine.
The compounds used as starting materials are known from
the literature in some cases or may be obtained by
methods known from the literature ~see Examples I to XXI
below).
As already mentioned, the new five-membered heterocycles
of formula I and the salts thereof, particularly the
physiologically acceptable salts thereof with inorganic
or organic acids or bases, have valuable pharmacological
properties, and in addition to having an inhibitory
effect on inflammation and bone degradation, they have
in particular antithrombotic, antiaggregatory and
tumour- or metastasis-inhibiting effects.
The compounds of formula I, wherein Ra is one of the
above-mentioned oxycarbonyl groups and/or Rb is one of
the above-mentioned ester groups, represent valuable
prodrugs.
Viewed from a further aspect the invention thus provides
a pharmaceutical composition comprising a compound of
formula I or a physiologically acceptable salt thereof,
, . . ... . ~ .. ,., ~ .. - - .
- 36 - 2 ~ 8
together with at least one physiologically acceptable
carrier or excipient.
Viewed from a still further aspect the invention also
provides the use of a compound of formula I or a
physiologically acceptable salt thereof for the
manufacture of a medicament for use in combatting
inflammation, bone degradation, tumours, metastases, and
aggregation-related conditions.
Viewed from a yet still further aspect the invention
provides a method of treatment of the human or non-
human, preferably mammalian, body to combat
inflammation, bone degradation, tumours, metastases, and
aggregation-related conditions, said method comprising -
administering to said body a compound of formula I or a -
physiologically acceptable salt thereof. -~
By way of example, compounds of formula I were
investigated for their biological effects as follows: `
2 1 ~ 8
- 37 -
1. Competitive binding of 3H-BIBU 52/test substance to
human thrombocytes:
A suspension of human thrombocytes in plasma is
incubated with 3H-BIBU 52 [(3S,5S)-5-[(4'-amidino-4-
biphenylyl)oxymethyl]-3-[(carboxyl)methyl]-2-
pyrrolidinone[3-3H-4-biphenylyl] - see DE-A-4214245],
which replaces the conventionally used 125I fibrinogen
ligand, and various concentrations of the substance to
be tested. The free and bound ligand are separated by
centrifuging and quantitatively determined by
scintillation counting. The inhibition of 3H-BIBU 52
binding by the test-substance is determined from the
measurements obtained.
In order to do this, donor blood is taken from an
anticubital vein and anticoagulated with trisodium
citrate (final concentration 13 mM~. The blood is
centrifuged for 10 minutes at 170 x g and the
supernatant platelet-rich plasma (PRP) is removed. The
remaining blood is vigorously centrifuged once more in
order to obtain plasma. The PRP is diluted 1:10 with
autologous plasma. 750 ~1 are incubated with 50 ~1 of
physiological saline solution, 100 ~1 of test substance
solution, 50 ~1 of 14C-sucrose (3700 Bq) and 50 ~1 of
3H-BIBU 52 (final concentration: 5 nM) at ambient
temperature for 20 minutes. In order to measure the
non-specific binding, 5 ~1 of BIBU 52 (final
concentration: 30 ~M) are used instead of the test
substance. The samples are centrifuged for 20 seconds
at 10000 x g and the supernatant is poured off. 100 ~1
thereof are measured in order to determine the free
ligand. The pellet is dissolved in 500 ~1 of 0.2N NaOH,
450 ~1 are mixed with 2 ml of scintillator and 25 ~1 of
5N HCl and measured. The residual plasma remaining in
the pellet is determined from the 14C-content and the
bound ligand is determined from the 3H-measurement.
- 38 - 2 1 ~ 4 1 ~
After the non-specific binding has been deducted, the
pellet activity is plotted against the concentration of
the test substance and the concentration for a 50%
inhibition of binding is determined.
2. Antithrombotic activitY -
Method
The thrombocyte aggregation is measured using the method
of Born and Cross (J. Physiol. 170: 397 (1964)) in
platelet-rich plasma taken from healthy volunteers. To
inhibit coagulation the blood is mixed with 3.14% sodium
citrate in a volume ratio of 1:10.
Collaqen-induced aaareaation
The pattern of the decrease in optical density of the
platelet suspension is photometrically measured and
recorded after the addition of the aggregation-
triggering substance. The rate of aggr~gation is
determined from the angle of inclination of the density
curve. The point on the curve where there is maximum
light transmittance is used to calculate the optical
density.
The concentration of collagen used is as small as -
possible but sufficient to produce an irreversible
reaction curve. Standard commercial collagen produced
by Hormonchemie of Munich is used.
Before the addition of the collagen the plasma is
incubated for 10 minutes with the substance at 37~C.
From the concentration/activity curve an EC50 is
determined, which describes the concentration giving a
50% change in the optical density in terms of the
2~17~
- - 39 -
inhibition of aggregation.
The following table shows the results which were
obtained:
Substance Competitive binding Inhibition of
(Example No.) of 3H-BIBU 52/test platelet
substance to humanaggregation
thrombocytes EC50 [nM]
ICso [nM]
224000.0 3000
2(3)550.0 380
3 400.0 880
3(1)6800.0 4400
3(3) 1.6 40
510.0 320
5(3)11.0 100
The compounds according to the invention are well
tolerated because on intravenous administration of
30 mg/kg of the compounds of Examples 5 and 5(3) to
three mice in each case, no animals died.
Furthermore, for example, an 80% inhibition of collagen
induced human thrombocyte aggregation is achieved ex
vivo with the rat plasma obtained 3 hours after peroral
administration of lO mg/kg of the compound of Example
2(19).
~ '
In the light of their inhibitory effect on cell-cell or
cell-matrix interactions, compounds of formula I and the
physiologically acceptable addition salts thereof are
suitable for treating or preventing diseases in which
smaller or greater cell aggregates occur or in which
cell-matrix interactions play a part, e.g. in treating
or preventing venous and arterial thrombosis,
- ~;. - ,: -: . -
.. ; ~. .
- 40 - 211417~ -
cerebrovascular diseases, lung embolism, cardiac
infarction, arteriosclerosis, osteoporosis and the
metastasis of tumours and the treatment of genetically
caused or acquired disorders of cell interactions with
one another or with solid structures. They are also
suitable for parallel therapy in thrombolysis with
fibrinolytics or vascular interventions such as
transluminal angioplasty or in the treatment of shock,
psoriasis, diabetes and inflammation.
For treating or preventing the diseases mentioned above
the dosage is between 0.1 ~g and 30 mg/kg of body
weight, preferably 1 ~g to 15 mg/kg of body weight,
given in up to 4 doses per day. For this purpose the
compounds according to the invention, optionally in
conjunction with other active substances such as -
thromboxane-receptor-antagonists and thromboxane
synthesis inhibitors or combinations thereof, serotonin
antagonists, ~-receptor antagonists, alkylnitrates such
as glycerol trinitrate, phospho-diesterase inhibitors,
prostacyclin and the analogues thereof, fibrinolytics
such as tPA, prourokinase, urokinase, streptokinase, or
anticoagulants such as heparin, dermatane sulphate,
activated protein C, vitamin K antagonists, hirudine, ~ -
inhibitors of thrombin or other activated clotting
factors, may be incorporated together with one or more
inert conventional carriers and/or diluents, e.g. corn
starch, lactose, sucrose, microcrystalline cellulose,
magnesium stearate, polyvinylpyrrolidone, citric acid,
tartaric acid, water, water/ethanol, water/glycerol,
water/sorbitol, water/polyethyleneglycol,
propyleneglycol, stearylalcohol, carboxymethylcellulose
or fatty substances such as hard fat or suitable
mixtures thereof, into conventional galenic preparations
such as plain or coated tablets, capsules, powders,
suspensions, solutions, sprays or suppositories.
21~17~
- 41 -
The Examples which follow are provided to illustrate the
invention in a non-limiting fashion.
All ratios and percentages are by weight unless
otherwise specified except for eluant ratios which are
by volume.
2 1 ~
- 42 -
Exam~le I
4-(4-piperidyl)-benzoic acid hydrochloride
To a solution of 63.0 g of 1-acetyl-4-phenyl-
piperidine in 1000 ml of methylene chloride, 157.4 g
of oxalyl chloride are added dropwise at -10 to -20C,
whilst stirring thoroughly. Then 46.7 g of aluminium
chloride are added. The mixture is stirred for 1 hour
at -10C and a further 82.7 g of aluminium chloride are
added. After another 2 hours the cooling bath is
removed and the mixture is stirred for 24 hours at
ambient temperature. The reaction solution is carefully
stirred into about 4 litres of ice/water and the aqueous
phase is extracted twice with methylene chloride. The
combined organic phases are washed with water, dried
with sodium sulphate and the solvent is removed under
reduced pressure. The remaining residue is dissolved in
2.5 litres of 2N sodium hydroxide solution whilst -~
stirring vigorously. To the dark aqueous solution, ice
is added and the solution is acidified with concentrated
hydrochloric acid. The precipitate is suction filtered
off, washed with water and refluxed for 5 hours in 2
litres of 6N hydrochloric acid. The solvent is removed
under reduced pressure. The remaining solid matter is
triturated with a little water and suction filtered.
Yield: 40.5 g (54 % of theory),
Melting point: > 300C
Rf value: 0.07 (silica gel; methylene chloride/methanol/
conc. ammonia = 4:1:0.25)
ExamPle II
4-[1-(tert.Butyloxycarbonyl)-4-piperidyl]-benzoic acid
-
To 16.4 g of sodium hydroxide in 300 ml of water, 47.5 g
of 4-(4-piperidyl)-benzoic acid hydrochloride is added.
- 43 - 2~178
The suspension is diluted with 500 ml of dioxane and 250
ml of water. Then 54.6 g of di-tert.butyl pyrocarbonate
are added in batches. The mixture is stirred for 16
hours at ambient temperature. The precipitate is
suctioned filtered and the filtrate is partly
concentrated by evaporation under reduced pressure. The
precipitate and the remaining aqueous filtrate are
combined and diluted with 1 litre of water. The aqueous
phase is set to pH 2 with saturated potassium hydrogen
sulphate solution and extracted twice with ethyl
acetate. The combined ethyl acetate phases are washed
with saturated sodium chloride solution, dried over
sodium sulphate and the solvent is removed under
reduced pressure. The crystalline crude product is
triturated with a little ethyl acetate, suction filtered
and dried.
Yield: 54.0 g (90% of theory),
Melting point: 172-174~C
Rf value: 0.73 (silica gel; ethyl acetate/cyclohexane =
4 : 1 )
Example III
4-[1-(tert.Butyloxycarbonyl)-4-piperidyl]-benzoic acid-
hydrazide
To a solution of 21.3 g of 4-[1-(tert.butyloxycarbonyl)-
4-piperidyl]-benzoic acid in 150 ml dimethylformamide,
9.6 g of l-hydroxy-(lH)-benzotriazole and 17.4 g of
N,N'-dicyclohexylcarbodiimide are added at -10C. The
mixture is stirred for 15 minutes at -10C, the cooling
bath is remo~ed and the temperature is allowed to
increase to ambient temperature. This reaction solution
is then added dropwise to a solution of 50 ml of 80%
hydrazine-hydrate in 150 ml dimethylformamide, cooled to
-10C. The mixture is stirred for 16 hours at ambient
temperature and the precipitate is suction filtered.
~, ~, ................... - . . . - - - . ~ . . . -
. : . : , . . . . . .
_ 44 _ 21i417 8
The filtrate is concentrated under reduced pressure.
Water is added to the residue and the aqueous phase is
extracted three times with ethyl acetate. The combined
organic phases are dried over sodium sulphate and the
solvent is concentrated by evaporation under reduced
pressure. The remaining solid material is
chromatographed over silica gel using ethyl
acetate/cyclohexane (4:1). 18.5 g of a crystalline
solid material is obtained which is triturated with -
ethyl acetate and then suction filtered.
Yield: 12.7 g (57% of theory)
Melting point: 151-154C
Rf value: 0.26 (silica gel; ethyl acetate/cyclohexane a
4:1) -
.: ', ' '
Example IV
N-[4-[1-(tert.Butyloxycarbonyl)-4-piperidyl]-benzoyl]-N'-
[(methoxycarbonyl)-carbonyl]-hydrazine
To a solution of 3.2 g of 4-[1-(tert.butyloxycarbonyl)-4-
piperidyl]-benzoic hydrazide and 1.7 g of
ethyldiisopropylamine in 50 ml of anhydrous
tetrahydro~uran, a solution of 1.3 g of oxalic acid-
monomethylester-chloride in 10 ml of anhydrous
tetrahydrofuran is added dropwise whilst cooling in an
ice bath. The mixture is stirred for 16 hours at ambient
temperature, the precipitate is suction filtered and the
filtrate is concentrated under reduced pressure. The
residue is dissolved in ethyl acetate and washed once
, using 0.5 N hydrochloric acid. The organic phase is
I dried and the solvent is evaporated under reduced
pressure. The crude product is chromatographed over
silica gel using ethyl acetate/cyclohexane (4:1).
Yield: 3.5 g (86% of theory)
Melting point: 105-108C
j Rf value: 0.27 (silica gel; ethyl acetate/cyclohexane
- 45 - 2~ 7~
= 4:1)
The following compounds are obtained in an analogous
manner:
(1) N-[4-[1-(tert.butyloxycarbonyl)-4-piperidyl]-benzoyl]-
N'-[[4-(methoxycarbonyl)-butyl]-carbonyl]-hydrazine
Adipic acid-monomethylester-chloride is used.
Melting point: 150-153C -
Rf value: 0.26 (silica gel; ethyl acetate/cyclohexane
= 4:1)
(2) N-[4-[4-(tert.butyloxycarbonyl)-4-piperidyl]-benzoyl]-
N'-[[cis-4-(methoxycarbonyl)-cyclohexyl]-carbonyl]-
hydrazine
cis-4-(methoxycarbonyl)-cyclohexanecarboxylic acid
chloride is used.
Rf value: 0.20 (silica gel; methylene chloride/
methanol = 20:1)
(3) N-[4-[4-(tert.butyloxycarbonyl)-4-piperidyl]-benzoyl]-
N'-[[trans-4-(methoxycarbonyl)-cyclohexyl]-carbonyl]-
hydrazine
A cis/trans-mixture of 4-(methoxycarbonyl)-cyclo-
hexanecarboxylic acid chloride is used. The
trans-product precipitates from the organic phase.
Melting point: 198-201DC
Rf value: 0.20 (silica gel; methylene chloride/
methanol = 20:1)
.
(4) N-[4-[1-(tert.butyloxycarbonyl)-4-piperidyl~-benzoyl]-
N'-t[trans-4-(ethoxycarbonyl)-cyclohexyl]-carbonyl~-
hydrazine
Rf value: 0.53 (silica gel; methylene chloride/methanol
= 9:1)
(5) N-[4-(1-benzyl-4-piperazinyl)-benzoyl]-N'-[[trans-
4-(ethoxycarbonyl)-cyclohexyl]-carbonyl]-hydrazine
- 46 - 21~ 8 : ~-
Melting point: 182-184C
Rf value: 0.78 (silica gel; methylene chloride/methanol
= 9:1)
(6) N-[[1-[1-(tert.butyloxycarbonyl)-4-pipe.ridyl]-4-
piperidyl]carbonyl]-N'-[[trans-4-(ethoxycarbonyl)-
cyclohexyl]-carbonyl]-hydrazine -
Melting point: 222-224C (decomp.)
Rf value: 0.79 (silica gel; methylene chloride/methanol
= 9:1)
Example V
2-[4-[1-(tert.Butyloxycarbonyl)-4-piperidyl]-phenyl]-5-
methoxycarbonyl-1,3,4-thiadiazole
A solution of 3.32g of N-[4-[1-(tert.butyloxycarbonyl)-
4-piperidyl]-benzoyl]-N-[(methoxycarbonyl)-carbonyl]-
hydrazine and 3.64g of 2,4-bis-(4-methoxyphenyl)-
1,3-dithia-2,4-diphosphetane-2,4-disulphide (Lawesson's
Reagent) in 60 ml tetrahydrofuran is heated to reflux for
30 minutes. The solvent is removed under reduced pressure `
and the residue is chromatographed over silica gel using
ethyl acetate/cyclohexane (2~
Yield: 2.75 g (83% of theory),
Melting point: 143-146~C
Rf value: 0.59 (silica gel; ethyl acetate/cyclohexane
= 1: 1)
ExamDle VI
2-~4-[1-(tert.Butyloxycarbonyl)-4-piperidyl]-phenyl]-5-
carboxy-1,3,4-thiadiazole
: -
A solution of 2.7 g of 2-[4-[1-(tert.butyloxycarbonyl)-4-
piperidyl~-phenyl]-5-methoxycarbonyl-1,3,4-thiadiazole and
1.1 g of lithium hydroxide-hydrate in 50 ml of
tetrahydrofuran and 40 ml of water is stirred for 30
`` 21141~
- 47 -
minutes at ambient temperature. The reaction solution is
neutralised with lN hydrochloric acid (pH 6.63). The
solvent is evaporated under reduced pressure and the
residue triturated with a little water and suction
filtered.
Yield: 2.25 g (87% of theory),
Rf value: 0.42 (silica gel; methylene chloride/methanol/
conc.ammonia = 4:1:0.25)
Example VII
4-t2-Amino-2-(methoxycarbonyl)-ethyl]-1-[6-(4-cyanophenyl)
-3-pyridazinyl~-imidazole-dihydrochloride
To a suspension of 1.55 g of 55% dispersion of sodium
hydride in mineral oil in 50 ml of anhydrous
dimethylformamide, a solution of 9.6 g of N-~-
tert.butyloxycarbonyl-L-histidine-methylester in 100 ml of
dry dimethylformamide is added dropwise under nitrogen
atmosphere at 0C. The mixture is stirred for 30 minutes
at 0C and then a solution of 7.6 g of 3-chloro-6-(4-
cyanophenyl)-pyridazine in 400 ml of dry dimethylformamide ~
is added dropwise. The mixture is stirred for 2 hours at
0C and 16 hours at ambient temperature. The reaction
solution is poured on to an ice/sodium chloride solution
and the aqueous phase is extracted three times using ethyl
acetate. The combined organic phases are dried over
sodium sulphate and the solvent is evaporated under
reduced pressure. The residue is chromatographed over
silica gel using methylene chloride/methanol (20:1).
After the removal of the solvent, the resultant crude
product (11.0 g) is dissolved in 500 ml of dioxane. 150
ml of ether saturated with hydrogen chloride is added and
the precipitate is suction filtered. The solid substance
is dissolved in a mixture of 750 ml of dioxane, 750 ml of
methanol and 250 ml of ether saturated with hydrogen
chloride and stirred for 16 hours at ambient temperature.
Then, the precipitate is suction filtered and washed with
- : ~ 211~17~ ~
- 48 -
dioxane (yield 4.4 g). By concentrating the mother liquor
to about lO0 ml and suction-filtering the precipitate, a
further 4.7 g of the product are obtained.
Total yield: 9.1 g (61% of theory),
Melting point: Sintering from 220C
Rf value: 0.43 (silica gel; methylene chloride/methanol/
conc. ammonia = 9:1:0.1)
Exam~le VIII
4-[2-(n-Butanesulphonylamino)-2-(methoxycarbonyl)-ethyl]-
l-[6-(4-cyanophenyl)-3-pyridazinyl]-imidazole
To a solution of 4.2 g of 4-[2-amino-2-(methoxycarbonyl)-
ethyl]-1-[6-(4-cyanophenyl)-3-pyridazinyl]-imidazole-
dihydrochloride and 4.5 g ethyldiisopropylamine in 150 ml
of methylene chloride, a solution of 2.0 g of n-
butanesulphonylchloride in 20 ml of dimethylformamide is ~ -
added dropwise at 0C. The mixture is stirred for 2 days
at ambient temperature and the precipitate is suction
filtered. The filtrate is washed twice with water. The
organic phase is dried over sodium sulphate and the
solvent is evaporated under reduced pressure. The residue
is triturated with a little methanol and suction filtered.
Yield: 0.85 g (18% of theory),
Rf value: 0.49 (silica gel; methylene chloride/methanol/
conc. ammonia = 9:1:0.1)
Exam~le IX
1-(tert.Butyloxycarbonyl)-4-(2-cyanoethyl)-piperidine
A suspension of 4.61 g of 1-(tert.butyloxycarbonyl)-
4-[2-(methanesulphonyl)-ethyl]-piperidine, 10.5 g of
potassion cyanide and a spatula tip of sodium iodide in 10
ml of anhydrous dimethylformamide are stirred for 16 hours
at ambient temperature. After adding a few ml of
dimethylformamide the mixture is heated for 7 hours to
-` 211~178
- 49 -
70C. To the cooled suspension, ice water and 3 ml of 2N
sodium hydroxide solution are added, the aqueous phase is ~ -~
extracted several times using tert.butyl-methylether. The
combined organic phases are washed with ice water and
saturated with sodium hydroxide solution and dried over
sodium sulphate. The solvent is evaporated under reduced
pressure.
Yield: 3.1 g (86% of theory), yellowish oil
Rf value: 0.63 (silica gel; cyclohexane/ethyl acetate
= 1:1)
Example X
1-(tert.Butyloxycarbonyl)-4-[2-(aminothiocarbonyl)-ethyl]-
piperidine
Hydrogen sulphide is passed for a few minutes at a
temperature of -5 to 0C through-a solution of 3.0 g -
of 1-(tert.butyloxycarbonyl)-4-(2-cyanoethyl)-
piperidine in 15 ml of pyridine and 1.15 ml of tri-
ethylamine. The reaction solution is stirred for 16 hours -
at 0C and a further 24 hours at ambient temperature.
Then, nitrogen is passed through the reaction solution for
3 hours, the solution is poured into 150 ml of ice/water -
mixture and the aqueous phase is extracted twice using
tert.butyl-methyl-ether. The combined organic extracts
are successively washed twice with water, once with 2N
citric acid solution, once with water and once with
saturated sodium chloride solution. The organic phase is
dried and the solvent is evaporated under reduced
pressure. A yellow oil is obtained which is mixed with a
little cyclohexane. After adding petroleum ether the
mixture is cooled in the ice/water bath and the colourless
crystalline precipitate is suction filtered.
Yield: 550 mg (16~ of theory),
Melting point: 148-154C
Rf value: 0.28 (silica gel; cyclohexane/ethyl acetate
= 1:1)
f'~
- 50 - 211417~
The following compound is obtained analogously to that of
Example X:
(1) 4-(benzyloxy)-benzoic acid thioamide
The reaction solution is poured into water and the
precipitate is suction filtered. The solid substance is
dissolved in ethyl acetate and the solution is dried over
sodium sulphate. After concentrating the solution under
reduced pressure, the product is precipitated.
Melting point: 172-174C
Rf value: 0.57 (silica gel; methylene chloride/ethyl
acetate = 9:1) -~
Exam~le XI
Ethyl-3-t4-(2-chloroacetyl)-phenyl]-propionate
To 56.0 g of aluminium trichloride in 150 ml of
dichlorethane, 23.7 g of chloroacetylchloride is added
dropwise at 0C. Then, 35.6 g of ethyl 3-phenyl-
propionate are added dropwise whilst the temperature is
maintained between -5 and 5C. The mixture is stirred for `
3 hours at ambient temperature. The reaction suspension
is poured into a mixture of ice and 30 ml of concentrated
hydrochloric acid, the phases are separated and the
aqueous phase is extracted twice with chloroform. The
combined organic phases are washed with water and dried
over magnesium sulphate. The solvent is evaporated under
reduced pressure, stirred with petroleum ether and suction
filtered.
Yield: 44.2 g ~87% of theory),
Rf value: 0.73 (silica gel; cyclohexane/ethyl acetate
= 1:1)
211~7~
- 51 -
Example XII
2-[4-(Benzyloxy)-phenylJ-4-[2-(methoxycarbonyl)-ethyl]-
1,3-thiazole
A solution of 14.0 g of 4-(benzyloxy)-benzoic
acid-thioamide and 12.0 g of methyl 4-bromo- -
3-oxo-butanoate in 1000 ml methanol is heated for 24 hours
until refluxing. The solvent is evaporated under reduced
pressure and the residue is distributed between methylene
chloride and dilute sodium carbonate solution. The -
organic phase is extracted once with dilute sodium -
carbonate solution and once with water, dried over sodium
sulphate and the solvent is evaporated under reduced
pressure. The residue is recrystallised from methanol.
Yield: 15.0 g (74% of theory),
Melting point: 80C
Rf value: 0.25 (silica gel; methylene chloride/ethyl ;~
acetate = 19:1)
Exam~le XIII
4-(2-Carboxyethyl)-2-(4-hydroxyphenyl)-1,3-thiazole
. .
A solution 8.0 g of 2-[4-(benzyloxy)-phenyl]-4-[2-
(methoxycarbonyl)-ethyl]-1,3-thiazole in 200 ml of glacial
acetic acid and 40 ml of methanol (saturated with hydrogen -
chloride) is hydrogenated in the presence of 4.0 g of 10~
palladium on charcoal for 1.5 hours at ambient temperature
and a hydrogen pressure of 5 bar. The catalyst is
filtered off and the filtrate is concentrated under
reduced pressure. The residue is heated with ethyl
acetate until boiling, cooled and the precipitate is
suction filtered.
Yield: 5.4 g (96% of theory),
Melting point: 224-226C
Rf value: 0.53 (silica gel; toluene/dioxane/ethanol/glacial
acetic acid = 9:1:1:0.6) -~
- 52 - 211~178
Example XIV
2-(4-Hydroxyphenyl)-4-[2-(methoxycarbonyl)-ethyl]-1,3-
thiazole
A solution of 5.0 g 4-(2-(carboxyethyl)-2-(4-hydroxy-
phenyl)-1,3-thiazole in 100 ml methanol and 10 ml of
methanol (saturated with hydrogen chloride) is stirred for
16 hours at ambient temperature. The solvent is
concentrated under reduced pressure. The residue is
heated in about 100 ml of water over a steam bath, then
cooled in an ice bath and the precipitate is suction
filtered. ~-
Yield: 4.2 g (79% of theory),
Melting point: 103-105C
Rf value: 0.33 (silica gel; cyclohexane/ethyl acetate
= 2:1)
Example XV
4-t4-[2-(Ethoxycarbonyl)-ethyl]-phenyl]-2-methyl-imidazole
A suspension of 5.1 g of ethyl 3-[4-(2-chloro-
acetyl)-phenyl]-propionate, 2.3 g of
acetamidine-hydrochloride and 4.7 g of sodium carbonate in
20 ml of anhydrous ethanol are heated to reflux for 2
hours. The solvent is evaporated under reduced pressure
and the residue is distributed between ethyl acetate and
water. The organic phase is washed three times with
water, dried over magnesium sulphate and the solvent is
evaporated under reduced pressure. The residue is
chromatographed over a uminium oxide (activity stage II)
using cyclohexane/ethyl acetate (3:7).
Yield: 900 mg (17% of theory),
Rf value: 0.23 (AloxN; ethyl acetate/cyclohexane = 7:3)
- 53 ~ 2 1 14~7 8
Example XVI
[4-(1-Benzyl-4-piperazinyl)-benzoyl]-hydrazine
3 g of N-[4-(1-benzyl-4-piperazinyl)-benzoyl]-N'- ~`
(tert.butyloxycarbonyl)-hydrazine are dissolved in 30 ml
of methylene chloride, mixed with 15 ml of trifluoro ~-
acetic acid and stirred for 4 hours at ambient `
temperature. The mixture is concentrated, evaporated
twice with acetone and the residue is distributed between
2N sodium hydroxide solution and ethyl acetate. The ethyl i~
acetate phases are concentrated and the residue is
purified over silica gel (eluant: methylene
chloride/methanol = 40:1 to 25:1).
Yield: 0.82 g (36% of theory),
Melting point: 168-170C
Rf value: 0.51 (silica gel; methylene chloride/methanol
= 9: 1) '
Exam~le XVII
N-t4-(1-Benzyl-4-piperazinyl)-benzoyl]-N'-(tert.butyloxy-
carbonyl)-hydrazine ~`
3 g of 4-(1-benzyl-4-piperazinyl)-benzoic-acid are
dissolved with warming in 100 ml of dimethylformamide and
mixed with 1.05 ml of chlorodiphenylphosphine. The
mixture is then cooled, 1.5 ml of triethylamine is added, ~`
and the mixture is stirred for 1 hour under ice cooling. -
It is mixed with 1.4 g of tert.butyloxycarbonyl-hydrazine,
stirred for 5 days at ambient temperature and
concentrated. The residue is mixed with ethyl acetate and
extracted with water, whilst the resultant solid product
is filtered off. The ethyl acetate phases are washed with
sodium bicarbonate solution and concentrated. The residue
is crystallised from ethyl acetate/petroleum ether.
Yield: 0.94 g (23% of theory),
_ 54 _ 2~4~7 8
Melting point: 162-165C
Rf value: 0.45 (silica gel; methylene chloride/methanol
= 9:1)
Exam~le XVIII
4-(1-Benzyl-4-piperazinyl)-benzoic acid
A mixture of 29.8 g of 4-(1-benzyl-4-piperazinyl)-benzoic
acid nitrile, 48 g of potassium hydroxide and 200 ml of
glycol are heated to reflux for 8 hours. The glycol is
largely distilled off in vacuo. The residue is mixed with
water, acidified with glacial acetic acid and the
preciptated product is filtered off and washed with
acetone.
Yield: 31.4 g (99~ of theory),
Melting point : 225-227C
Rf value: 0.57 (silica gel; methylene chloride/methanol
= 9:1)
Example XIX
4-(1-Benzyl-4-piperazinyl)-benzoic acid-nitrile
26 g of 4-fluoro-benzonitrile, 37.3 ml of N-
benzylpiperazine and 36.7 ml N-ethyl-diisopropylamine are
heated together for 8 hours at 140C. The mixture is then
poured onto water and extracted using methylene chloride.
The organic phase is concentrated and the residue is
crystallised from ether/petroleum ether.
Yield: 29.8 g (50% of theory),
Melting point : 106-108C
Rf value: 0.89 (silica gel; methylene chloride/methanol
= 9:1)
- 55 - 2~17~ ~ ~
Example XX
[[1-[1-(tert.Butyloxycarbonyl)-4-piperidyl]-4-piperidyl]-
carbonyl]-hydrazine
1 g of 1-[l(tert.butyloxycarbonyl)-4-piperidyl]-
4-ethoxycarbonyl-piperidine and lO ml hydrazine hydrate
are heated to reflux in 20 ml of methanol for 4 hours.
The mixture is concentrated and the residue triturated
using ether.
Yield: 0.72 g (76% of theory), ~ -
Rf value: 0.42 (silica gel; methylene chloride/methanol -~
= 4:1)
Example XXI
~[1-[1-(tert.Butyloxycarbonyl)-4-piperidyl]-4-ethoxy-
carbonyl-piperidine -
A mixture of 24.9 g of 1-tert.butyloxycarbonyl-4-
piperidone, 19.3 g of ethyl piperdine-4-carbonate and ;
46.5 ml of` titanium(IV)-isopropoxide are stirred for 1
hour at ambient temperature, mixed with 170 ml of ethanol
and 5 g of sodium cyanborohydride and stirred for 20
hours at ambient temperature. 34 ml of water is added,
the mixture is filtered, the filtrate is concentrated,
extracted with ethyl acetate and concentrated by
evaporation. The residue is purified chromatographically
(silica gel, eluant, cyclohexane/ethyl acetate = 2:3).
Yield: 32.9 g (77% of theory),
Rf value: 0.44 (silica gel; ethyl acetate)
.~,.',:,: '
- 56 - 21~17~
Exam~le 1
2-[4-[1-(tert.Butyloxycarbonyl)-4-piperidyl]-phenyl]-5-
[[2-(methoxycarbonyl)-ethyl]-aminoca~bonyl]-1,3,4-
thiadiazole
A solution of 2.0 g of 2-[4-[1-(tert.butyloxycarbonyl)-4-
piperidyl]-phenyl]-5-carboxy-1,3,4-thiadiazole, 1.77 g of
2-[(lH)-benzotriazol-1-yl]-1,1,3,3-tetramethyluronium-
tetrafluoroborate, 0.72 g of~-alanine-methylester-
hydrochloride, 0.75 g 1-hydroxy-(lH-)
benzotriazole and 1.4 g of N-methyl-morpholine in
50 ml of dimethylformamide is stirred for 5 hours at
ambient temperature. The solvent is removed under
reduced pressure. Water is added to the residue and the
aqueous phase is extracted using ethyl acetate. The
organic phase is dried over sodium sulphate and the
solvent is removed under reduced pressure. The crude
product is chromatographed over silica gel using
methylene chloride/methanol (9:1), and the product
obtained after removing the solvent is triturated with
ethyl acetate and suction filtered.
Yield: 1.5 g (62% of theory),
Melting point: 176-178C,
Rf value: 0.76 (silica gel; ethyl acetate/cyclohexane
= 4:1)
Exam~le 2
2-~[2-(Methoxycarbonyl)-ethyl]-aminocarbonyl]-5-[4-(4-
piperidyl)-phenyl]-1,3,4-thiadiazole-hydrochloride
A solution of 1.4 g of 2-[4-[1-(tert.butyloxycarbonyl)-4-
piperidyl)-phenyl]-5-[[2-(methoxycarbonyl)-ethyl]-amino-
carbonyl]-1,3,4-thiadiazole in 40 ml of dioxane and 40 ml
of ether saturated with hydrogen chloride is stirred for
2.5 hours at ambient temperature. The precipitate is --~-~
suction filtered and washed with ether.
~, . , . :
- 57 _ 21~178
Yield: 1.05 g (85% of theory),
Melting point: 250-255C,
Massspectrum: M~ = 374
Rf value: 0.16 (silica gel; methylene chloride/
methanol/conc. ammonia = 9:1:0.1)
The following compounds are obtained analogously:
(1) 2-[4-(Methoxycarbonyl)-butyl]-5-[4-(4-piperidyl)-
phenyl]-1,3,4-thiadiazole-hydrochloride
Mass spectrum: (M+H)~ = 360
Rf value: 0.70 (silica gel; methylene chloride/
methanol/conc.ammonia = 4:1:0.25)
(2) 2-[cis-4-(Methoxycarbonyl)-cyclohexyl]-5-[4-(4-
piperidyl)-phenyl]-1,3,4-thiadiazole-hydrochloride
Methanol saturated with hydrogen chloride is added to the
reaction solution. After stirring for 1 hour at ambient
temperature, the solvent is evaporated under reduced
pressure.
Mass spectrum: M = 385
Rf value: 0.45 (silica gel; methylene chloride/
methanol/conc. ammonia = 4:1:0.25)
(3) 2-[trans-4-(Methoxycarbonyl)-cyclohexyl]-5-[4-(4- ;
piperidyl)-phenyl]-1,3,4-thiadiazole-hydrochloride
The reaction is carried out in a 1:1:1 mixture consisting
of dioxane, ether (saturated with hydrogen chloride) and
methanol (saturated with hydrogen chloride). After
stirring for 3 hours, the precipitate is suction filtered
and washed with ether.
Mass spectrum: M~ = 385
Rf value: 0.67 (silica gel; methylene chloride/
methanol/conc. ammonia = 4:1:0,25)
(4) 2-[trans-4-(Methoxycarbonyl)-cyclohexyl]-4-[4-(4-
piperidyl)-phenyl]-imidazole-dihydrochloride ~ -
21~4178
- 58 ~
(5) 2-[trans-4-tMethoxycarbonyl)-cyclohexyl]-4-[3,4-
dehydro-4-piperidyl]-phenyl]-1,3-thiazole-hydrochloride
(6) 2-[[3-(methoxycarbonyl)-propyl]amino]-4-[4-(4-
piperidyl)phenyl]-1,3-thiazole-dihydrochloride
(7) 2-[trans-4-(Methoxycarbonyl)-cyclohexyl]-5-[4-(1-
piperazinyl)-phenyl]-1,3,4-thiadiazole-dihydrochloride
(8) 4-[4-[2-(Ethoxycarbonyl)-ethyl]-phenyl]-2-[2-(4-
piperidyl)-ethyl]-1,3-thiazole-hydrochloride
(9) 4-[4-[2-(Methoxycarbonyl)-ethyl]-phenyl]-2-[2-(4-
piperidyl)-ethyl]-imidazole-dihydrochloride
(10) 4-[4-[2-(Methoxycarbonyl)-ethyl]-phenyl]-l-methyl-
2-[2-(4-piperidyl)-ethyl]-imidazole-dihydrochloride
(11) 4-[4-[2-(Ethoxycarbonyl)-ethyl]-phenyl]-2-methyl-1-
[2-(4-piperidyl)-ethyl]-imidazole-dihydrochloride-hydrate
The reaction is carried out in ethanol with the addition
of ethereal hydrochloric acid.
Rf value: 0.48 (Reversed Phase; RP8; methanol/5% saline
solution = 6:4)
Calc.x 1.95 HCl x H2O: C 57.82 H 7.70 N 9.15 Cl 14.95
Found : 57.62 7.68 9.16 15.07
(12) 2-t4-[2-(Methoxycarbonyl)-ethyl]-phenyl]-l-methyl-
4-[(3-pyrrolidinyl)-oxymethyl]-imidazole-dihydrochloride
(13) 4-[4-[2-(Methoxycarbonyl)-ethyl]-2-[N-[(4-
piperidyl)-carbonyl]-N-methyl-amino]-1,3-thiazole-
hydrochloride
(14) 2-[4-[2-(Methoxycarbonyl)-ethyl]-phenyl]-4-[(4-
piperidyl)-aminocarbonyl]-1,3-thiazole-hydrochloride
::
. i'~ " s ,,, ' ~ ",' ,,; ~
211417~
- 59 -
(15) 2-[2-(Methoxycarbonyl)-ethyl]-4-[4-[N-[(4-piperidyl)
-carbonyl]-N-methyl~amino]-phenyl]-1,3-thiazole-hydro-
chloride
(16) 2-[2-(Methoxycarbonyl)-ethyl]-5-[2-[2-(4-piperidyl)-
ethyl]-5-pyrimidinyl]-1,3,4-thiadiazole-hydrochloride
(17) 4-[2-(Methoxycarbonyl)-ethyl]-2-[4-[(4-piperidyl)-
methyloxy]-phenyl]-1,3-thiazole-dihydrochloride-dihydrate -
The reaction is carried out with methanol saturated with
hydrogen chloride. The precipitate is suction filtered
and washed with tert.butyl-methyl-ether.
Melting point: 95-98~C
Rf value: 0.28 (Reversed Phase; RP8; methanol/5% saline
solution = 6:4) --
(18) 4-t4-[(Methoxycarbonyl)-methyloxy]-phenyl]-2-[2- -
[(4-piperidyl)-ethyl]-1,3-thiazole-hydrochloride
(19) 2-[trans-4-(Ethoxycarbonyl)-cyclohexyl]-5-[4-(4-
piperidyl)-phenyl]-1,3,4-thiadiazol-hydrochloride
The reaction is carried out in a 2:1 mixture of methylene
chloride and trifluoroacetic acid. The product is
treated with a mixture of ethanol and ethereal
hydrochloric acid.
Melting point: 274-280C (decomp.)
Rf value: 0.41 (silica gel; methylene chloride/methanol
= 9:1)
(20) 2-[trans-4-(Ethoxycarbonyl)-cyclohexyl]-5-[1-(4-
piperidyl)-4-piperidyl]-1,3,4-thiadiazole-hydrochloride.
The reaction is carried out analogously to Example 2(19).
Melting point: >320~
Rf value: 0.67 (Reversed Phase Plate RP18; methanol/
5% saline solution = 6:4)
21~417~
- 60 -
Example 3
2-[(2-Carboxyethyl)-aminocarbonyl]-5-[4-(4-piperidyl)-
phenyl]-1,3,4-thiadiazole-hydrochloride
A suspension of 550 mg of 2-[[2-(methoxycarbonyl)-ethyl]-
aminocarbonyl]-5-[4-(4-piperidyl)-phenyl]-1,3,4-
thiadiazole-hydrochloride in 100 ml of 6N hydrochloric
acid is stirred for 3 hours at ambient temperature.
After adding a further 500 ml of 6N hydrochloric acid,
the solution is stirred for another hour. The solvent is
removed under reduced pressure and the crude product is
triturated with a little water and suction filtered.
Yield: 480 mg (91% of theory),
Mass spectrum: M~ = 360
Rf value: 0.06 (silica gel; methylene chloride/
methanol/conc. ammonia = 4:1:0.25)
The following compounds are obtained analogously:
(1) 2-(4-Carboxybutyl)-5-[4-(4-piperidyl)-phenyl]-1,3~4-
oxadiazole
The crude product is purified by chromatography.
Mass spectrum: M~ = 329
Rf value: 0.35 (silica gel; methylene chloride/methanol/
conc. ammonia = 2:1:0.25)
(2) 2-(cis-4-Carboxycyclohexyl)-5-[4-(4-piperidyl)-
phenyl]-1,3,4-thiadiazole-hydrochloride
Melting point: > 310~C
Mass spectrum: M~ = 371
value: 0.17 (silica gel; methylene chloride/methanol/
conc. ammonia = 4:1:0.25)
(3) 1-[6-(4-Amidino-phenyl)-3-pyridazinyl]-4-[2-(n-butane
-sulphonylamino)-2-carboxy-ethyl]-imidazole-hydrochloride
21~4~78
- 61 -
Mass spectrum: (M+H)+ = 472
Rf value: 0.20 (silica gel; methylene chloride/methanol/
conc. ammonia = 2:1:0.25)
(4) 4-[4-(2-Carboxy-ethyl)-phenyl]-2-[2-(4-piperidyl)- :~ ~
ethyl]-1,3-thiazole -
The product of Example 9 is heated in 3N hydrochloric
acid for 1 hour on a steam bath.
Melting point: Decomposition from 168C
Rf value: 0.38 (Reversed Phase RP8; methanol/5% saline
solution = 6:4) -
(5) 2-(trans-4-Carboxycyclohexyl)-4-[4-(4-piperidyl)-
phenyl]-imidazole-dihydrochloride
(6) 2-(trans-4-Carboxycyclohexyl)-l-methyl-4-[4-(1-methyl
-4-piperidyl)-phenyl]-imidazole-dihydrochloride
(7) 2-(trans-4-Carboxycyclohexyl)-l-methyl-4-[4-(4-
piperidyl)-phenyl]-imidazole-dihydrochloride
(8) 2-(trans-4-Carboxycyclohexyl)-4-[4-(3,4-dehydro-4- ~i .
piperidyl)-phenyl]-1,3-thiazole-hydrochloride ~
(9) 2-[(3-Carboxypropyl)-amino~-4-[4-(4-piperidyl)- ~.
phenyl]-1,3-thiazole-dihydrochloride .
(10) 2-(trans-4-Carboxycyclohexyl)-5-[4-(1-piperazinyl)- :~
phenyl~-1,3,4-thiadiazole-dihydrochloride : :
(11) 4-t4-(2-Carboxy-ethyl)-phenyl~-2-[2-(4-piperidyl)-
ethyl~-imidazole-dihydrochloride -~
(12) 4-[4-(2-Carboxy-ethyl)-phenyl~-l-methyl-2-[2-(4-
piperidyl)-ethyl]-imidazole-dihydrochloride
(13) 4-[4-(2-Carboxy-ethyl)-phenyl]-2-methyl-1-[2-(4-
- 62 - 2114178
piperidyl)-ethyl]-imidazole-dihydrochlorid-hydrate
Rf value: 0.64 (Reversed Phase RP8; methanol/5~ saline
solution = 6:4)
Calc. x 1.95 HCl x 0.6 H2O:
C 56.77 H 7.37 N 9.84 Cl 16.40
Found: 56.77 7.13 9.93 16.34
(14) 2-[4-(2-Carboxy-ethyl)-phenyl]-1-methyl-4-[(3-
pyrrolidinyl)-oxymethyl]-imidazole-dihydrochloride
(15) 4-[4-(2-Carboxy-ethyl)-phenyl]-2-[N-[(4-piperidyl)-
carbonyl]-N-methyl-amino~-1,3-thiazole-hydrochloride
(16) 2-[4-(2-Carboxy-ethyl)-phenyl]-4-[(4-piperidyl)-
aminocarbonyl]-1,3-thiazole-hydrochloride
:,, ", ~,, ,
(17) 2-(2-Carboxy-ethyl)-4-[4-[N-[(4-piperidyl)-carbonyl]
-N-methyl-amino]-phenyl]-1,3-thiazole-hydrochloride
(18) 2-(2-Carboxy-ethyl)-5-[2-[2-(4-piperidyl)-ethyl]-5-
pyrimidinyl]-1,3,4-thiadiazole-hydrochloride
~ .
(19) 1-[3-(4-Amidino-phenyl)-6-pyridazinyl]-3-[2-
carboxy-2-(phenylsulfonylamino)-ethyl]-indole-hydro-
chloride
(20) 2-(4-Amidino-phenyl)-4-[4-[2-(acetylamino)-2-
carboxy-ethyl]-phenyl]-5-methyl-1,3-thiazole-
hydrochloride
(21) 4-(4-Amidino-phenyl)-2-[4-[2-(methanesulfonylamino)-
2-carboxy-ethyl]-phenyl]-1-methyl-imidazole-hydrochloride
(22) 4-(2-Carboxy-ethyl)-2-[4-[(4-piperidyl)-methyloxy]-
phenyl]-1,3-thiazole-dihydrochloride-hydrate
Melting point: decomposition from 225C
Rf value: 0,36 (Reversed Phase, RP8; methanol/5% saline
- 63 - 21~4178
solution = 6:4)
~ '."
(23) 4-[4-(CarboxymethylQxy)-phenyl]-2-[2-(4-piperidyl)-
ethyl]-1,3-thiazole-hydrochloride
(24) 4-[4-(2-Carboxy-ethyl)-phenyl]-2-[2-(4-pyridyl)-
ethyl]-1,3-thiazole-hydrochloride
(25) 4-[4-(2-Carboxy-ethyl)-cyclohexyl]-1-[2-(4-
quinuclidinyl)-ethyl]-2-methyl-imidazole-dihydrochloride
(26~ 2-t4~ enzyl-4-piperazinyl)-phenyl]-5-(trans-4-
carboxycyclohexyl)-1,3,4-thiadiazole
Mass spectrum: M~ = 462
Rf value: 0.15 (Reversed Phase Plate RP18; methanol/5%
sodium chloride solution = 6:4)
(27) 2-(trans-4-Carboxycyclohexyl)-5-[1-(4-piperidyl)-4-
piperidyl]-1,3,4-thiadiazole
Melting point: > 320~C
Rf value: 0.67 (Reversed Phase Plate RP18; methanol 5%
sodium chloride solution = 6:4)
.
ExamPle 4
2-t4-tl-(tert.13utyloxycarbonyl)-4-piperidyl)-phenyl]-5- ,.
t4-(methoxycarbonyl)-butyl]-1,3,4-thiadiazole
A solution of 2.4 g of N-t4-tl-(tert.butyloxycarbonyl)-4-
piperidyl]-benzoyl]-N'-tt4-(methoxycarbonyl)-butyl]-
carbonyl]-hydrazine and 2.1 g of 2,4-bis-(4-
methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-
disulphide (Lawesson's Reagent) in 40 ml of
tetrahydrofuran is heated to reflux for 30 minutes. The
solvent is then evaporated off under reduced pressure and
the residue is chromatographed over silica gel.
Yield: 2.4 g (quant~tative),
..... . , .. . . . . , . . ... .... . , ., . , ,, , ~, , ,, ~ ,,
- 64 - 2~178
Melting point: 111-113C,
Mass spectrum: M~ = 459
Rf value: 0.38 (silica gel; ethyl acetate/cyclohexane
The following compounds are obtained analogously:
-....,~
(1) 2-[4-[1-(tert.Butyloxycarbonyl)-4-piperidyl]-phenyl]-
5-tcis-4-(methoxycarbonyl)-cyclohexyl]-1,3,4-thiadiazole
Melting point: 130-132C
Mass spectrum: M~ = 485
Rf value: 0.49 (silica gel; ethyl acetate/
cyclohexane = 1:1)
(2) 2-[4-[1-(tert.Butyloxycarbonyl)-4-piperidyl]-phenyl]-
5-[trans-4-(methoxycarbonyl)-cyclohexyl]-1,3,4-
thiadiazole :.
Melting point: 180-182C
Rf value: 0.57 (silica gel; cyclohexane/ethyl acetate ..
= 1:1) ,
(3) 2-[4-[4-(tert.Butyloxycarbonyl)-l-piperazinyl]-
phenyl]-5-[trans-4-(methoxycarbonyl)-cyclohexyl]-1,3,4- . :
thiadiazole :~:
(4) 2-[4-[1-(tert.Butyloxycarbonyl)-4-piperidyl]-phenyl]-
5-[trans-4-(ethoxycarbonyl)-cyclohexyl]-1,3,4-thiadiazole
Melting point: 164-166C :
Rf value: 0.78 (silica gel; methylene chloride/methanol
= 9 1) `-
. ~. ' ~:
(5) 2-[trans-4-(Ethoxycarbonyl)-cyclohexyl~-5-[4-(1-
benzyl-4-piperazinyl)-phenyl]-1,3,4-thiadiazole
Melting point: 166-170C : `~
Rf value: 0.63 (silica gel; methylene chloride/methanol
= 9 ~
- 65 - 211A178
(6) 2-[1-[1-(tert.Butyloxycarbonyl)-4-piperidyl]-4-
piperidyl]-5-[trans-4-(ethoxycarbonyl)-cyclohexyl]-1,3,4-
thiadiazole
Rf value: 0.49 (silica gel; methylene chloride/methanol
= 9:1)
Example 5
2-(4-Carboxy-butyl)-5-[4-(4-piperidyl)-phenyl]-1,3,4- -
thiadiazole-hydrochloride ~ ;
A solution of 1.0 g of 2-[4-(methoxycarbonyl)-butyl]-5-
[4-(4-piperidyl)-phenyl]-1,3,4-thiadiazole-hydrochloride
and 0.22 g of lithium hydroxide-hydrate in 30 ml
tetrahydrofuran and 24 ml of water is stirred for 60
minutes at ambient temperature. The reaction solution is
acidified with lN hydrochloric acid. Excess
tetrahydrofuran is evaporated off under reduced pressure
and the precipitate is suction filtered and washed with a
little water.
Yield: 0~80 g (83% of theory), -~ -
Mass spectrum: M~ = 345
Rf value: 0.18 (silica gel; methylene chloride/methanol/
conc. ammonia = 4:1:0.25)
The following compounds are obtained analogously
(1) 3-(4-Carboxy-cyclohexyl)-4-phenyl-5-[4-(4-piperidyl)-
phenyl]-1,2,4-triazole
After acidification the solvent mixture is evaporated off
under reduced pressure and the crude product is
chromatographed over silica gel.
Mass spectrum: M~ = 430
Rf value: 0.12 (silica gel; methylene chloride/methanol/
conc. ammonia = 4:1:0.25)
(2) 3-(4-Carboxy-butyl)-4-phenyl-5-[4-(4-piperidyl)-
- 66 - 211~17~
phenyl]-1,2,4-triazole
After acidification the solvent mixture is evaporated off
under reduced pressure and the crude product is
chromatographed over silica gel.
Mass spectrum: M~ = 404
Rf value: 0.24 (silica gel; methylene chloride/methanol/
conc. ammonia = 2:1:0.25) ~ -
(3) 2-(trans-4-Carboxy-cyclohexyl)-5-[4-(4-piperidyl)-
phenyl]-1,3,4-thiadiazole-hydrochloride
Mass spectrum: M~ = 371
Rf value: O.o9 (silica gel; methylene chloride/methanol/
conc. ammonia = 4:1:0.25)
-: .
(4) 2-(4-Carboxy-cyclohexyl)-5-[4-(4-piperidyl)-phenyl]-
1,3,4-oxadiazole -
After acidification the solvent mixture is evaporated off
under reduced pressure and the crude product is
chromatographed over silica gel.
Mass spectrum: M~ = 355
Rf value: O.o9 (silica gel; methylene chloride/methanol/
conc. ammonia = 4:1:0.25)
(5) 2-(trans-4-Carboxy-cyclohexyl)-5-[4-(2,2,6,6-
tetramethyl-4-piperidyl)-phenyl]-1,3,4-thiazole-
hydrochloride
(6) 2-(trans-4-Carboxy-cyclohexyl)-4-[4-(4-cyano-4-
piperidyl)-phenyl]-l-methyl-imidazole-dihydrochloride
Example 6 --
2-[4-(Methoxycarbonyl)-butyl]-5-[4-(4-piperidyl)-phenyl]- --
1,3,4-oxadiazole
~.,
A solution of 2.0 g of N-[4-[1-(tert.butyloxycarbonyl)-4- -
piperidyl]-benzoyl]-N'-[[4-(methoxycarbonyl)-butyl]-
~ . .
- 211~
- 67 -
carbonyl]-hydrazine and 0.3 ml of pyridine in 18 ml
thionyl chloride is stirred for 3 hours at ambient
temperature. Then it is heated to reflux for 45 minutes.
Excess thionyl chloride is evaporated off under reduced
pressure, the residue is mixed with toluene and the
solvent again evaporated off under reduced pressure. The
residue is chromatographed over silica gel.
Yield: 0.24 g (15 % of theory),
Mass spectrum: M~ = 343
Rf value: 0.16 (silica gel; methylene chloride/methanol/
conc. ammonia = 8:1:0.1)
,
The following compound is obtained analogously:
(1) 2-[4-(Methoxycarbonyl)-cyclohexyl]-5-[4-(4-piperidyl)
-phenyl]-1,3,4-oxadiazole
Mass spectrum: M~ = 369
Rf value: 0.24 (silica gel; methylene chloride/
methanol/conc. ammonia = 9:1)
Example 7
3-[4-(Methoxycarbonyl)-cyclohexyl]-4-phenyl-5-[4-(4-
piperidyl)-phenyl]-1,2,4-triazole
To a solution of 785 mg of aniline in 5 ml of 1,2-
dichlorobenzene, 220 mg phosphorus trichloride are added
and the mixture is heated briefly to 60C. Then 700 mg
of N-[4-[4-(tert.-butyl-oxycarbonyl)-4-piperidyl]-
benzoyl]-N'-[tcis-4-(methoxycarbonyl)-cyclohexyl]-
carbonyl]-hydrazine are added and the mixture is heated
to reflux for 2.5 hours. The solvent is evaporated off
under reduced pressure. Water and lN sodium hydroxide
solution are added to the residue until the solution
becomes alkaline. The aqueous phase is extracted once
with methylene chloride and once with ethyl acetate. The
combined organic phases are dried over sodium sulphate
21~17~ ~
- 68 -
and the solvent is evaporated off under reduced pressure.
The residue is chromatographed over silica gel.
Yield: 550 mg (86 % of theory),
Mass spectrum: (M+H)' = 445 -
Rf value: 0.36 (silica gel; methylene chloride/methanol/
conc. ammonia = 4:1:0.25)
The following compound is obtained analogously
(1) 3-[4-(Methoxycarbonyl)-butyl]-4-phenyl-5-[4-(4-
piperidyl)-phenyl]-1,2,4-triazole
Rf value: 0.34 (silica gel; methylene chloride/methanol/
conc. ammonia = 4:1:0.25)
Example 8 -
. .
l-t6-(4-Amidino-phenyl)-3-pyridazinyl]-4-[2-(n-
butanesulphonylamino)-2-(methoxycarbonyl)-ethyl]-
imidazole
:
To a solution of 700 mg of 4-[2-(n-butanesulphonylamino)-
2-(methoxycarbonyl)-ethyl]-1-[6-(4-cyanophenyl)-3-
pyridazinyl~-imidazole in 250 ml of anhydrous methanol,
is introduced hydrogen chloride at 0C for 1 hour whilst
stirring. After stirring for 16 hours at ambient
temperature, the solvent is evaporated off under reduced
pressure at a bath temperature of 30C. The residue is
dissolved in 50 ml of anhydrous methanol and after adding
3 g of ammonium carbonate, stirred for 4 hours at ambient
temperature. The precipitate is suction filtered and
washed again with anhydrous methanol. The filtrate is
concentrated by evaporation under reduced pressure and
the residue is chromatographed over silica gel.
Yield: 250 mg (34 % of theory),
Melting point: 227-229C
Mass spectrum: (M+H)~ = 486
R~ value: 0.09 (silica gel: methylene chloride/methanol/
9 21~178 -
-- 6
conc. ammonia = 4:1:0.2S)
The following compounds are obtained analogously:
(1) 1-[3-[4-Amidino-phenyl]-6-pyridazinyl]-3-[2-
(methoxycarbonyl)-2-(phenylsulfonylamino)-ethyl]-indole
(2) 4-[4-[2-(Acetylamino)-2-(methoxycarbonyl)-ethyl]-
phenyl~-2-(4-amidino-phenyl)-5-methyl-1,3-thiazole
(3) 4-[4-Amidino-phenyl]-l-methyl-2-[4-[2-(methane-
sulphonylamino)-2-(methoxycarbonyl)-ethyl]-phenyl]-
imidazole
Example 9
2-[2-[1-(tert.Butyloxycarbonyl)-4-piperidyl]-ethyl]-4-[4-
[2-(ethoxycarbonyl)-ethyl]-phenyl]-1,3-thiazole
A solution of 550 mg of 1-(tert.butyloxycarbonyl)-4-(2-
thio-amido-ethyl)-piperidine and 530 mg of ethyl 3-[4-
(2-chloroacetyl)-phenyl]-propionate in 30 ml of methanol
are heated to reflux for 14 hours. Then 500 mg of ethyl
diisopropylamine and a solution of 500 mg of di-tert.-
butyl pyrocarbonate in ether are added dropwise at
ambient temperature. The mixture is stirred for 10
minutes at ambient temperature and the solvent is removed
at reduced pressure. The residue is chromatographed over
silica gel.
Yield: 300 mg (32 % of theory),
Rf value: 0.26 (silica gel; cyclohexane/ethyl
acetate = 8:2)
- 70 -
Exam~le 10 - 211~178
2-[4-[[1-(tert.Butyloxycarbonyl)-4-piperidyl]-methyloxy]-
phenyl]-4-[2-(methoxycarbonyl)-ethyl]-1,3-thiazole
To a solution of 4.09 g of 2-(4-hydroxy-phenyl)-4-[2-
(methoxycarbonyl)-ethyl)-1,3-thiazole in 1000 ml of - -~
anhydrous dimethylformamide, are added 1.7 g of
potassium-tert.butoxide and stirred for 15 minutes at
ambient temperature. 4.5 g of l-(tert.butyloxy- -
carbonyl)-4-(mesyloxymethyl)-piperidine are added and the
mixture is heated for 24 hours to 60C. After the
addition of a further 0.9 g of potassium-tert.butoxide
and 2.2 g of 1-(tert.butyloxy-carbonyl)-4-
(mesyloxymethyl)-piperdine, the stirring is continued for -
2 days at 60C. The solvent is evaporated off at reduced
pressure, and the remaining residue is chromatographed -
over silica gel.
Yield: 4.3 g (68 % of theory),
Melting point: 75-77C
Rf value: 0.70 (silica gel; methylene chloride/ethyl
acetate = 4:1) -
Exam~le 11
1-[2-tl-(tert.Butyloxycarbonyl)-4-piperidyl]-ethyl]-4-[4-
[2-(ethoxycarbonyl)-ethyl]-phenyl]-2-methyl-imidazole - ~
.: .
A suspension of 820 mg of 4-[4-[2-(ethoxycarbonyl)-
ethyl]-phenyl]-2-methyl-imidazole and 140 mg of 55%
sodium hydride in mineral oil in 5 ml of
dimethylformamide is stirred for 30 minutes at ambient
temperature. 980 mg of 1-(tert.butyloxycarbonyl)-4-[2-
~methanesulfonyloxy)-ethyl]-piperidine are added and the
mixture is stirred for 2 hours at ambient temperature.
The solvent is evaporated off under reduced pressure and
the residue is distributed between water and ethyl
- 71 - 211~17~ :
acetate. After neutralising the aqueous phase with 2N
citric acid, the aqueous phase is extracted several times
using ethyl acetate. The combined ethyl acetate phases
are washed with water, dried over magnesium sulphate, and
the solvent is evaporated off under reduced pressure.
The residue is chromatographed over alumunium oxide
(activity stage III), using cyclohexane/ethyl acetate
( 1 : 1) .
Yield: 650 mg (43 % of theory),
Rf value: 0.29 (Aluminium oxide N; cyclohexane/ethyl
acetate = 1:1)
Example 12
2-ttrans-4-(Isobutyloxycarbonyl)-cyclohexyl]-5-[4-(4-
piperidyl)-phenyl]-1,3,4-thiadiazole-hydrochloride
Through a stirred suspension of 0.5 g of 2-(trans-4-
carboxycyclohexyl)-5-[4-(4-piperidyl)-phenyl]-1,3,4-
thiadiazole-hydrochloride in 25 ml of isobutanol,
hydrogen chloride gas is passed for 1.5 hours. The
stirring is continued for 16 hours at ambient
temperature. The mixture is concentrated, the residue is
triturated with acetone and suction filtered.
Yield: 0.54 g (95 % of theory),
Melting point: 265-267C
Rf value: 0.63 (Reversed Phase Plate RP18: methanol/5%
sodium chloride solution = 6:4)
The following compound is obtained analogously:
(1) 2-ttrans-4-(Isopropyloxycarbonyl)--cyclohexyl]-5-t4-
(4-piperidyl)-phenyl]-l~3~4-thiadiazole-hydrochloride
Rf value: 0.67 (silica gel; methylenechloride/methanol/
conc.
ammonia = 4:1:0.25)
- 72 - 21~78
Exam~le 13
.
2-(trans-4-Carboxy-cyclohexyl)-5-~4-(1-piperazinyl)-
phenyl]-1,3,4-thiadiazole
' .':
0.08 g of 2-[4-(1-Benzyl-4-piperazinyl)-phenyl]-5-(trans-
4-carboxycyclohexyl)-1,3,4-thiadiazole in 30 ml of
dimethylformamide are treated with hydrogen at a pressure
of 4 bar in the presence of 0.5 g of palladium hydroxide
on charcoal for 7 days at ambient temperature.
Rf value: 0.29 (Reversed Phase Plate RP18; methanol/5%)
sodium chloride solution = 6:4)
The following compound is obtained analogously: -
(1) 2-~trans-4-(Ethoxycarbonyl)-cyclohexyl]-5-[4
(l-piperazinyl)-phenyl]-1,3,4-thiadiazole-hydrochloride
Mass spectrum: M~ = 400 ;
Rf value: 0.35 (silica gel; methylene chloride/
methanol = 9:1) ~ -
Example 14
', ~,:..
Dry ampoule containing 2.5 mg of active substance per 1
ml
-'.
:
Composition:
:.
Active substance 2.5 mg
Mannitol 50.0 mg
Water for injections ad 1.0 ml
'
Preparation:
The active substance and mannitol are dissolved in water.
After transferring the solution to the ampoule it is
freeze dried. At the point of use, the solution is made
- 73 - 211~178
up with water for injections.
Example 15
Dry ampoule containing 35 mg of active substance per 2 ml
.
Composition:
Active substance35.0 mg
Mannitol 100.0 mg
~ater for injections ad 2.0 ml
Preparation:
The active substance and mannitol are dissolved in water.
After transferring the solution to the ampoule, it is
freeze-dried.
At a point of use, the solution is made up with water for
injections
Exam~le 16
Tablet containing 50 mg of active substance
_
Composition:
(1) Active substance50.0 mg
(2) Lactose 98.0 mg
(3) Corn starch 50.0 mg
(4) Polyvinylpyrrolidone15.0 mg
(5) Magnesium stearate2.0 mq
215.0 mg ~ :
Preparation: :
Components (1), (2) and (3) are mixed and granulated with
- 74 - ~ 7 8
an aqueous solution of component (4). Component (5) is
added to the dried granules. From this mixture, tablets
are compressed, biplanar, facetted on both sides and
notched on one side. Diameter of tablets: 9 mm.
Exam~le 17
Tablet with 350 mg of active substance
Composition:
(1) Active substance350.0 mg
(2) Lactose 136.0 mg -
(3) Corn starch80.0 mg
(4) Polyvinylpyrrolidone 30.0 mg
(5) Magnesium stearate 4.0 ma
600.0 mg
Components (1), (2) and (3) are mixed and granulated with
an aqueous solution of component (4). Component (5) is
added to the dried granules. From this mixture, tablets
are compressed, biplanar, facetted on both sides and
notched on one side.
Diameter of tablets: 12 mm. ;~
Exam~le 18 -~
Capsules containing 50 mg of active substance
'
Composition:
(1) Active substance50.0 mg
(2) Dried corn starch58.0 mg
(3) Powdered lactose50.0 mg
(4) Magnesium stearate 2.0 mg
160.0 mg
2~178
- 75 -
Preparation:
Component (1) is triturated with component (3). This
triturate is added to the mixture of components (2) and
(4) with thorough mixing.
This powdered mixture is packed into size 3 hard gelatine
oblong capsules in a capsule filling machine.
Example 19
Capsules containing 350 mg of active substance
Composition:
(1) Active substance 350.0 mg
(2) Dried corn starch 46.0 mg
(3) Powdered lactose 30.0 mg
(4) Magnesium stearate 4.0 ma
430.0 mg
Preparation:
Component (1) is triturated with component (3). This
triturate is added to the mixture of components (2) and
(4), with thorough mixing. This powdered mixture is
packed into size O hard gelatine oblong capsules in a
capsule filling machine.