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S017002pct.200
WO 98/37075 PCT/EP98/00865
Disubstituted bicyclic hete:rocycles, the preparation and
the use thereof as pharmaceutical compositions
The present invention relates. to new disubstituted bicyclic
heterocycles of general formula
--~ Ra - A - Het - H. - Ar - E , ( I )
the tautomers, stereoisomers and mixtures thereof and the
salts thereof, particularly the physiologically acceptable
salts thereof with organic or inorganic acids or bases
which have valuable properties.
The compounds of general fortr~ula I above wherein E denotes
a cyano group are valuable intermediates for preparing the
other compounds of general formula I, and the compounds of
general formula I above wherein E denotes an RbNH-C(=NH)-
group, and the tautomers and stereoisomers thereof have
-- useful pharmacological properties, particularly a thrombin-
inhibiting activity and the effect of extending thrombin
time.
The present application thus relates to the new compounds
of general formula I above and the preparation thereof,
pharmaceutical compositions containing the
pharmacologically active comF~ounds and the use thereof.
In the above general formula
A denotes a carbonyl or sulph.onyl group linked to the
benzo, pyrido, pyrimido, pyrazino, pyridazino or thieno
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moiety of the group Het, whilst moreover the abovementioned
moieties may not contain an R., group,
B denotes an ethylene group, wherein a methylene group,
linked either to the group Het or Ar, may be replaced by an
oxygen or sulphur atom or by a sulphinyl, sulphonyl,
carbonyl or -NR1 group, wherein
R1 denotes a hydrogen atom or a C1_6-alkyl group,
E denotes a cyano or RbNH-C(=NH)- group wherein
Rb denotes a hydrogen atom, a hydroxy group, a
Cl_3-alkyl group or a group which may be cleaved in
vi vo,
Ar denotes a phenylene or naphthylene group optionally
substituted by a fluorine, chlorine or bromine atom or by a
trifluoromethyl, Cl_3-alkyl or Cl_3-alkoxy group,
a thienylene, thiazolylene, pyridinylene, pyrimidinylene,
pyrazinylene or pyridazinylene group optionally substituted
in the carbon skeleton by a C1_3-alkyl group,
Het denotes a bicyclic heterocycle of formula
X
Y Il , , wherein
X is a nitrogen atom and
Y is an oxygen or sulphur atom or a nitrogen atom
optionally substituted by a Cl_6-alkyl or
C3_,-cycloalkyl group, whilst additionally one or two
non-angular methyne groups in the phenyl moiety of the
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above-mentioned bicyclic heterocycle may each be
replaced by a nitrogen atom,
or X denotes a methyne group optionally substituted by
the group R1, wherein R1 is as hereinbefore defined,
and
Y denotes a nitrogen atom optionally substituted by a
C,_6-alkyl or C,_,-cycloal~:yl group,
or Het denotes a group of the formula
R1
'N I
\ ~ i
N
R1
Nw O
I ~ ,
N
R1
N
,~- s
I ,
rr
R1
\ Z
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D
G or
w
R1
~~ N
wherein
N
R1
R1 is as hereinbefore defined,
Z denotes an oxygen or ~~ulphur atom,
one of the groups D or C~ denotes a nitrogen atom and
the other group D or G denotes a methyne group,
and Ra denotes a Cl_6-alkyl group, a C3_.,-cycloalkyl group
optionally substituted by a C'1_3-alkyl group, wherein the
Cl_3-alkyl group may additionally be substituted by a
carboxyl group or by a group which may be converted in vivo
into a carboxy group,
or an R2NR3- group wherein
R2 denotes a C1_4-alkyl group, which may be substituted
by a carboxy, C1_6-alkylo~cycarbonyl, benzyloxycarbonyl,
C1_3-alkylsulphonylaminocarbonyl ,
phenylsulphonylaminocarbonyl, trifluorosulphonylamino,
trifluorosulphonylaminocarbonyl or 1H-tetrazolyl
group,
a CZ_q-alkyl group substituted by a hydroxy, phenyl-
Cl_3-alkoxy, carboxy-Cl_3-alkyl amino, Cl_3-
alkoxycarbonyl-Cl_3-alkylamino, N- (Cl_3-alkyl) -carboxy-
Cl_3-alkyl amino or N- (Cl_3-alkyl) -Cl_3-alkoxycarbonyl-Cl_3'
alkylamino group, whilst in the abovementioned groups
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the carbon atom in the a-position relative to the
adjacent nitrogen atom may not be substituted, or
a piperidinyl group optionally substituted by a
CI_3-alkyl group and
R3 denotes a hydrogen atom, a C1-6-alkyl group, a
C3_~-cycloalkyl group optionally substituted by a C1-3-alkyl
group, a C3-6-alkenyl or alkynyl group, wherein the
unsaturated part may not be linked directly to the nitrogen
atom of the RzNR3- group,
a phenyl group optionally substituted by a
fluorine, chlorine or bromine atom or by a C1_3-alkyl or
C1_3-alkoxy group, a benzyl, oxazolyl, isoxazolyl, thiazolyl,
isothiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl,
pyridazinyl, pyrrolyl, thienyl or imidazolyl group or
RZ and R3 together with the nitrogen atom between
them denote a 5- to 7-membered cycloalkyleneimino group,
optionally substituted by a carboxy or C1-4-alkoxycarbonyl
group, onto which a phenyl ring may additionally be fused.
According to one aspect of the present invention,
there is provided a disubstituted bicyclic heterocycle of
general formula
Ra - A - Het - B - Ar - E, ( I )
wherein A denotes a carbonyl or sulphonyl group linked to
the benzo, pyrido or thieno moiety of the group Het,
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B denotes an ethylene group in which the methylene group
linked to the group Ar is optionally replaced by an oxygen
or sulphur atom or by an -NR1- group, wherein R1 denotes a
hydrogen atom or a C1-4-alkyl group, E denotes an RbNH-C (=NH) -
group wherein Rb denotes a hydrogen atom, a hydroxy,
C1_9-alkoxycarbonyl, cyclohexyloxycarbonyl, phenyl-C1-3-
alkoxycarbonyl, benzoyl, p-C1-3-alkyl-benzoyl or pyridinoyl
group, whilst the ethoxy moiety in the 2-position of the
abovementioned C1_9-alkoxycarbonyl group is optionally
substituted by a C1-3-alkyl-sulphonyl or 2- (C1-3-alkoxy) -ethyl
group, Ar denotes a 1,4-phenylene group optionally
substituted by a chlorine atom or by a methyl, ethyl or
methoxy group or Ar denotes a 2,5-thienylene group, Het
denotes a 1-(C1-3-alkyl)-2,5-benzimidazolylene, 1-
cyclopropyl-2,5-benzimidazolylene, 2,5-benzothiazolylene, 1-
(C1-3-alkyl) -2, 5-indolylene, 1- (C1-3-alkyl) -2, 5-imidazo [4, 5-
b]pyridinylene, 3-(C1-3-alkyl)-2,7-imidazo[1,2-a]pyridinylene
or 1-(C1-3-alkyl)-2,5-thieno[2,3-d]imidazolylene group and Ra
denotes an R2NR3- group wherein R2 is a C1-4-alkyl group
optionally substituted by a carboxy, C1-6-alkyloxycarbonyl,
benzyloxycarbonyl, C1_3-alkylsulphonylaminocarbonyl or
1H-tetrazol-5-yl group, or a C2_4-alkyl group substituted by
a hydroxy, benzyloxy, carboxy-C1_3-alkylamino,
C1-3-alkoxycarbonyl-Cl-3-alkylamino, N- (C1-3-alkyl) -carboxy-
C1-3-alkylamino or N- (C1_3-alkyl) -C1-3-alkoxycarbonyl-
C1_3-alkylamino group, whilst in the abovementionied groups
the carbon atom in the a-position to the adjacent nitrogen
atom is not substituted, R3 denotes a C3_~-cycloalkyl group; a
propargyl group, wherein the unsaturated part is not linked
directly to the nitrogen atom of the R2NR3 group; a phenyl
group optionally substituted by a fluorine or chlorine atom,
or by a methyl o~ methoxy group, a pyrazoyl, pyridazolyl or
pyridinyl group optionally substituted by a methyl group or
RZ and R3 together with the nitrogen atom between them denote
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-5b-
a 5- to 7-membered cycloalkyleneimino group, optionally
substituted by a carboxy or C1-9-alkoxycarbonyl group, to
which a phenyl ring is optionally fused, or a tautomer,
stereoisomer or salt thereof.
According to another aspect of the present
invention, there is provided a disubstituted bicyclic
heterocycle of general formula I or tautomer, stereoisomer
or salt thereof as described herein, wherein R1 denotes a
hydrogen atom or a methyl group, Rb denotes a hydrogen atom;
a hydroxy, C1_9-alkoxycarbonyl, cyclohexyloxycarbonyl,
benzyloxycarbonyl, benzoyl, p-C1_3-alkylbenzoyl or nicotinoyl
group, whilst the ethoxy moiety in the 2-position of the
abovementioned C1-9-alkoxycarbonyl group is optionally
substituted by a C1_3-alkylsulphonyl or 2- (C1_3-alkoxy) -ethyl
group, Het denotes a 1-methyl-2,5-benzimidazolylene,
1-cyclopropyl-2,5-benzimidazolylene, 2,5-benzothiazolylene,
1-methyl-2,5-indolylene, 1-methyl-2,5-imidazo[4,5-
b]pyridinylene,3-methyl-2,7-imidazo[1,2-a]pyridinylene or
1-methyl-2,5-thieno[2,3-d]imidazolylene group, R2 denotes a
C1_3-alkyl group optionally substituted by a carboxy,
C1_6-alkoxycarbonyl, benzyloxycarbonyl,
methylsulphonylaminocarbonyl or 1H-tetrazol-5-yl group, a
CZ-3-alkyl group substituted by a hydroxy, benzyloxy,
carboxy-C1-3-alkylamino, C1-3-alkoxycarbonyl-C1_3-alkylamino,
N- (C1-3-alkyl) -carboxy-C1-3-alkylamino or N- (C1-3-alkyl) -
C1-3-alkoxycarbonyl-C1-3-alkylamino group, whilst in the
abovementioned groups the carbon atom in the a-position to
the adjacent nitrogen atom is not substituted, and R3 denotes
a propargyl group, wherein the unsaturated moiety is not
linked directly to the nitrogen atom of the R2NR3 group, a
phenyl group optionally substituted by a fluorine or
chlorine atom, or by a methyl or methoxy group, or R3 denotes
a py:ridinyl group.
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-5c-
According to still another aspect of the present
invention, there is provided a disubstituted bicyclic
heterocycle of general formula I or tautomer, stereoisomer
or salt thereof as described herein, wherein A denotes a
car~~onyl group linked to the benzo or thieno moiety of the
group Het, R1 denotes a hydrogen atom or a methyl group,
Rb is a hydrogen atom, a hydroxy, C1-9-alkoxycarbonyl,
cyclohexyloxycarbonyl, benzyloxycarbonyl, benzoyl,
p-Cl._3-alkyl-benzoyl or nicotinoyl group, whilst the ethoxy
moiety in the 2-position of the abovementioned
C1_9-alkoxycarbonyl group is optionally substituted by a
methylsulphonyl or 2-ethoxy-ethyl group, Ar denotes a
1,4-phenylene group optionally substituted by a methoxy
group or Ar denotes a 2,5-thienylene group, Het denotes a
1-methyl-2,5-benzimidazolylene, 2,5-benzothiazolylene,
1-methyl-2,5-indolylene or 1-methyl-2,5-thieno[2,3-
d]imidazolylene group and R2 denotes a C1-3-alkyl group
optionally substituted by a carboxy, C1_6-alkyloxycarbonyl,
benzyloxycarbonyl, methylsulphonylaminocarbonyl or
1H-tetrazol-5-yl group, or a C2_3-alkyl group substituted by
a hydroxy, benzyloxy, carboxy-C1_3-alkylamino,
C1_3-alkoxycarbonyl-Cl_3-alkylamino, N- (C1_3-alkyl) -carboxy-
C1_3-alkylamino or N- (C1_3-alkyl ) -C1_3-alkoxycarbonyl-
C1_3-alkylamino group, whilst in the abovementioned groups
the carbon atom in the a-position to the adjacent nitrogen
atom is not substituted, and R3 denotes a phenyl group
optionally substituted by a fluorine atom, or R3 denotes a
2-pyridinyl group.
The compounds of the above general formula I which
contain a group capable of being cleaved in vivo are thus
prodrugs and compounds of general formula I which contain
two groups capable of being cleaved in vivo are so-called
double prodrugs.
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-5d-
The phrase ~~a group which may be converted in vivo
intc a carboxy group" denotes, for example, a hydroxymethyl
group, a carboxy group esterified with an alcohol, in which
the alcoholic moiety is preferably a C1-6-alkanol, a phenyl-
s C1-3-alkanol, a C3_9-cycloalkanol, wherein a CS_8-cycloalkanol
may additionally be substituted by one or
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two Cl_,-alkyl groups, a CS_e-cycloalkanol, in which a
methylene group in the 3- or 4-position is replaced by an
oxygen atom or by an imino group optionally substituted by
a Cl_3-alkyl, phenyl-Cl_,-alkyl, phenyl-Cl_3-alkoxycarbonyl or
C2_6-alkanoyl group, and the cycloalkanol moiety may
additionally be substituted by one or two C1_3-alkyl groups,
a C,_.,-cycloalkenol, a C3_5-alkenol, a phenyl-C3_5-alkenol, a
C3_5-alkynol or phenyl-C,_5-alk~~nol, with the proviso that nc
bond to the oxygen atom emanates from a carbon atom which
carries a double or triple bond, a
C3_8-cycloalkyl-X1_3-alkanol, a bicycloalkanol having a total
of 8 to 10 carbon atoms, which may additionally be
substituted in the bicycloalkyl moiety by one or two
C1_3-alkyl groups, a 1,3-dihyd:ro-3-oxo-1-isobenzofuranol or
an alcohol of formula
R4-CO-O-(:R5CR6)-OH,
wherein
R4 denotes a Cl_e-alkyl, CS_.,-cycloalkyl, phenyl or
phenyl-Cl_3-alkyl group,
RS denotes a hydrogen atom, a Cl_3-alkyl, CS_.,-cycloalkyl
or phenyl group and
R6 denotes a hydrogen atom or a C1_3-alkyl group,
or the phrase "a group which may be cleaved in vivo from an
imino or amino group" denotes for example a hydroxy group,
an acyl group such as a benzoyl- or pyridinoyl group or a
C1-16-alkanoyl group such as t:he formyl-, acetyl-,
propionyl-, butanoyl-, pentanoyl- or hexanoyl group, an
allyloxycarbonyl group, a C1-1.6-alkoxycarbonyl group such
as the methoxycarbonyl-, etho~s:ycarbonyl-, propoxycarbonyl-,
isopropoxycarbonyl-, butoxycarbonyl-,
tert.-butoxycarbonyl-, pentox~~carbonyl-, hexoxycarbonyl-,
octyloxycarbonyl-, nonyloxycarbonyl-, decyloxycarbonyl-,
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undecyloxycarbonyl-, dodecyloxycarbonyl- or
hexadecyloxycarbonyl group, a. phenyl-C1_6-alkoxycarbonyl
group such as the benzyloxyca.rbonyl-, phenylethoxycarbonyl-
or phenylpropoxycarbonyl group, a C1_3-alkylsulphonyl-
C2_4-alkoxycarbonyl-, C1-3-alkoxy-C2_4-alkoxy-
C2-4-alkoxycarbonyl- or R4C0-O-(R5CR6)-O-CO-group, wherein
R4 to R6 are as hereinbefore defined.
Examples of preferred prodrug groups for a carboxy group
include a C1_6-alkoxycarbonyl group such as the
methoxycarbonyl, ethoxycarbonyl, n-propyloxycarbonyl,
,,....
isopropyloxycarbonyl, n-butyloxycarbonyl,
n-pentyloxycarbonyl, n-hexylo:xycarbonyl or cyc-
lohexyloxycarbonyl group or phenyl-C1_3-alkoxycarbonyl
group such as the benzyloxyca:rbonyl group and
for an imino or amino group a C1-g-alkoxycarbonyl group
such as the methoxycarbonyl, ethoxycarbonyl,
n-propyloxycarbonyl, isopropy:Loxycarbonyl,
n-butyloxycarbonyl, n-pentyloacycarbonyl,
n-hexyloxycarbonyl, cyclohexy:Loxycarbonyl,
n-heptyloxycarbonyl, n-octyloaycarbonyl or
n-nonyloxycarbonyl group, a phenyl-C1_3-alkoxycarbonyl
-.
group such as the benzyloxycarbonyl group, a phenylcarbonyl
group optionally substituted by a C1_3-alkyl group such as
the benzoyl or 4-ethyl-benzoyl group, a pyridinoyl group
such as the nicotinoyl group, a C1_3-alkylsulphonyl-
n-C2_3-alkoxycarbonyl or C1_3--alkoxy-C2_3-alkoxy-
C2_4-alkoxycarbonyl group such as the
2-methylsulphonylethoxycarbonyl or 2-(2-ethoxy)-
ethoxycarbonyl group.
Moreover, the saturated alkyl and alkoxy moieties
containing more than 2 carbon atoms as well as alkanoyl and
unsaturated alkyl moieties containing more than 3 carbon
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.. g -
atoms as mentioned in the foregoing definitions also
include the branched isomers thereof such as for example
the isopropyl, tert.-butyl and isobutyl group, etc.
Preferred compounds of the above general formula I,
however, are those wherein
A denotes a carbonyl or sulphonyl group linked to the
benzo, pyrido, pyrimido, pyra.zino, pyridazino or thieno
moiety of the group Het, whilst moreover the abovementioned
moieties may not contain an R.1 group,
B denotes an ethylene group, in which a methylene group,
linked either to the group Het or Ar, may be replaced by an
oxygen or sulphur atom or by a sulphinyl, sulphonyl,
carbonyl or -NR1- group, wheresin
Rl denotes a hydrogen atom or a Cl_5-alkyl group,
E denotes an RbNH-C(=NH)- group wherein
Rb denotes a hydrogen atc>m, a hydroxy group, a
Cl_3-alkyl group or a group which may be cleaved in
vi vo,
Ar denotes a phenylene group optionally substituted by a
fluorine, chlorine or bromine atom or by a trifluoromethyl,
Cl_3-alkyl or Cl_3-alkoxy group,
a thienylene, thiazolylene, pyridinylene, pyrimidinylene,
pyrazinylene or pyridazinylene group optionally substituted
in the carbon skeleton by a C,_3-alkyl group,
Het denotes a bicyclic heterocycle of formula
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_ g _
/ X
Y~' , wherein
X is a nitrogen atom and
Y is an oxygen or sulphur atom or a nitrogen atom
optionally substituted b;y a Cl_6-alkyl or
C3_,-cycloalkyl group, wh~~lst additionally one or two
non-angular methyne groups in the phenyl moiety of the
above-mentioned bicyclic heterocycle may each be
replaced by a nitrogen ai:om,
,...
or X denotes a methyne group optionally substituted by
the group R1, wherein R1 :is as hereinbefore defined,
and
Y denotes a nitrogen atom optionally substituted by a
Cl_6-alkyl or C3_,-cycloalkyl group,
or Het denotes a group of the formulae
/R1
".." / ~ N
N
Rl
N ~O
i ~ ,
N
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R1.
N ,'
S ~ ~~
-N
R1
~ ~ ,
' Z
D
G
or
R1
~~N
. wherein
N
R:L
Rl is as hereinbefore de:Eined,
Z denotes an oxygen or sulphur atom,
one of the groups D or G denotes a nitrogen atom and
the other group D or G denotes a methyne group,
and R8 denotes a Cl_6-alkyl grc>up, a C3_.,-cycloalkyl group
optionally substituted by a C1_3-alkyl group, wherein the
Cl_3-alkyl group may additiona:Lly be substituted by a
carboxyl group or by a group 'which may be converted in vivo
into a carboxy group,
or a RZNR3- group wherein
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- :L 1 -
R2 denotes a C,_,-alkyl group, which may be substituted
by a carboxy, C,_6-alkylo:~cycarbonyl, benzyloxycarbonyl,
C1_3-alkylsulphonylaminocarbonyl,
phenylsulphonylaminocarbonyl, trifluorosulphonylamino,
trifluorosulphonylaminocarbonyl or 1H-tetrazolyl
group,
a CZ_,-alkyl group substituted by a hydroxy, phenyl-
Cl_,-alkoxy, carboxy-Cl_3-alkylamino, Cl_3-
alkoxycarbonyl-Cl_3-alkylamino, N- (Cl_3-alkyl) -carboxy-
C,_3-alkyl amino or N- (Cl_3-alkyl) -Cl_3-alkoxycarbonyl-Cl_3-
,"", alkylamino group, whilst in the abovementioned groups
the carbon atom in the a--position relative to the
adjacent nitrogen atom may not be substituted, or
a piperidinyl group optic>nally substituted by a
Cl_3-alkyl group and
R3 denotes a hydrogen atom, a Cl_6-alkyl group, a
C3_,-cycloalkyl group optionally substituted by a
Cl_3-alkyl group, a C3_6-alkenyl or alkynyl group,
wherein the unsaturated part may not be linked
directly to the nitrogen atom of the RZNR3- group,
a phenyl group optionally substituted by a fluorine,
chlorine or bromine atom or by a C1_3-alkyl or
Cl_3-alkoxy group, a benzy:L, oxazolyl, isoxazolyl,
thiazolyl, isothiazolyl, :pyrazolyl, pyrrolyl, thienyl,
pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl,
imidazolyl or piperidinyl group or
Rz and R3 together with the nitrogen atom between them
denote a 5- to 7-membered cycloalkyleneimino group,
optionally substituted by a carboxy or
C1_,-alkoxycarbonyl group, onto which a phenyl ring may
additionally be fused, particularly those compounds
wherein
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Het denotes one of the abovementioned benzimidazolylene,
benzothiazolylene, benzoxazo].ylene, indolylene,
quinazolinylene, quinoxazolinonylene,
imidazo[4,5-b]pyridinylene, imidazo[1,2-a]pyridinylene,
thiazolo [5, 4-b] pyridinylene c>r thieno [2, 3-d] imidazolylene
groups,
the tautomers, the prodrugs, the double prodrugs, the
stereoisomers and the salts thereof.
Particularly preferred compounds of general formula I above
are those wherein
A denotes a carbonyl or sulphonyl group linked to the
benzo, pyrido, pyrimido, pyrazino, pyridazino or thieno
moiety of the group Het, whilst moreover the abovementioned
moieties may not contain an R1 group,
B denotes an ethylene group in which the methylene group
linked to the group Ar may be replaced by an oxygen or
sulphur atom or by an -NRl- group, wherein
R1 denotes a hydrogen atom or a Cl_4-alkyl group,
E denotes an RbNH-C(=NH)- group wherein
Rb denotes a hydrogen atom, a hydroxy,
C1_9-alkoxycarbonyl, cyclohexyloxycarbonyl, phenyl-
C1_3-alkoxycarbonyl, benzoyl, p-C1_3-alkyl-benzoyl or
pyridinoyl group, whilst the ethoxy moiety in the
2-position of the abovementioned C1_9-alkoxycarbonyl
group may additionally be substituted by a C1_3-alkyl-
sulfonyl or 2-(C1_3-alkoxy)-ethyl group,
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- :L 3 -
Ar denotes a 1,4-phenylene group optionally substituted by
a chlorine atom or by a methyl, ethyl or methoxy group or
it denotes a 2,5-thienylene group,
Het denotes a 1-(C1_3-alkyl)-2,5-benzimidazolylene, 1-
cyclopropyl-2,5-benzimidazolylene, 2,5-benzothiazolylene,
1-(C1_3-alkyl)-2,5-indolylene, 1-(C1_3-alkyl)-
2, 5-imidazo [4, 5-b] pyridinylen~e, 3- (C1_3-alkyl) -
2,7-imidazo[1,2-a]pyridinylen or 1-(Cl_3-alkyl)-
2,5-thieno[2,3-d]imidazolylene group and
Ra denotes an RZNR3- group wherein
Rz is a Cl_4-alkyl group substituted by a carboxy,
C1_6-alkyloxycarbonyl, benzyloxycarbonyl,
C1_3-alkylsulphonylaminocarbonyl or 1H-tetrazol-5-yl
group,
a C2_4-alkyl group substituted by a hydroxy, benzyloxy,
carboxy-C1_3-alkylamino, C'1_3-alkoxycarbonyl-
C1_3-alkylamino, N-(C1_3-alkyl)-carboxy-C1_3-alkylamino
or N-(C1_3-alkyl)-C1_3-alk:oxycarbonyl-Cl_3-alkylamino
"-.. group, whilst in the above:mentioned groups the carbon
atom in the a-position to the adjacent nitrogen atom
may not be substituted,
R3 denotes a C3_7-cycloalkyl group, a propargyl group,
wherein the unsaturated part may not be linked directly
to the nitrogen atom of the R2NR3 group, a phenyl group
optionally substituted by a fluorine or chlorine atom,
or by a methyl or methoxy group, a pyrazolyl, py-
ridazolyl or pyridinyl group optionally substituted by
a methyl group or
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R2 and R3 together with the nitrogen atom between them
denote a 5- to 7-membered. cycloalkyleneimino group,
optionally substituted by a carboxy or C1-4-alk-
oxycarbonyl group, to which a phenyl ring may
additionally be fused,
the tautomers, the stereoisomers and the salts thereof.
Most particularly preferred compounds of the above general
formula I are those wherein
'" A denotes a carbonyl or sulphonyl group linked to the
benzo, pyrido or thieno moiety of the group Het, whilst
moreover the abovementioned moieties may not contain an R1
group,
B denotes an ethylene group in which the methylene group
linked to the group Ar may be replaced by an oxygen or
sulphur atom or by an -NR1- group, wherein
R1 denotes a hydrogen atom or a methyl group,
E denotes an RbNH-C(=NH)- group, wherein
Rb denotes a hydrogen atom or a hydroxy,
Cl_9-alkoxycarbonyl, cyclohexyloxycarbonyl,
benzyloxycarbonyl, benzoyl, p-C1-3-alkyl-benzoyl or
nicotinoyl group, whilst the ethoxy moiety in the 2-
position of the abovement.ioned C,_9-alkoxycarbonyl
group may additionally be: substituted by a Cl_3-
alkylsulphonyl or 2- (Cl_3-alkoxy) -ethyl group,
Ar denotes a 1,4-phenylene group optionally substituted by
a chlorine atom or by a methyl, ethyl or methoxy group, or
it denotes a 2,5-thienylene group,
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- :L 5 -
Het denotes a 1-methyl-2,5-benzimidazolylene, 1-
cyclopropyl-2,5-benzimidazolylene, 2,5-benzothiazolylene,
1-methyl-2,5-indolylene, 1-methyl-
2,5-imidazo[4,5-b]pyridinylene, 3-methyl-
2,7-imidazo[1,2-a]pyridinylene or 1-methyl
2,5-thieno[2,3-d]imidazolylene group and
Ra denotes a R2NR3- group wherein
R2 denotes a C1_3-alkyl group which may be substituted
by a carboxy, Cl_6-alkyloxycarbonyl, benzyloxycarbonyl,
'~ methylsulphonylaminocarbonyl or 1H-tetrazol-5-yl group,
a C2_3-alkyl group substituted by a hydroxy, benzyloxy,
carboxy-C1_3-alkylamino, C1_3-alkoxycarbonyl-
C1_3-alkylamino, N-(C1_3-alkyl)-carboxy-C1_3-alkylamino
or N-(Cl_3-alkyl)-C1_3-alkoxycarbonyl-C1_3-alkylamino
group, whilst in the above:mentioned groups the carbon
atom in the a-position to the adjacent nitrogen atom
may not be substituted, and
R3 denotes a propargyl group, wherein the unsaturated
moiety may not be linked directly to the nitrogen atom
of the R2NR3 group, a phenyl group optionally
substituted by a fluorine or chlorine atom, or by a
methyl or methoxy group, or denotes a pyridinyl group,
particularly those wherein
A denotes a carbonyl group linked to the benzo or thieno
moiety of the group Het,
B denotes an ethylene group wherein the methylene group
attached to the group Ar may be replaced by an -NR1 group,
wherein
CA 02277949 1999-07-14
- 16 -
R1 denotes a hydrogen atom or a methyl group,
E denotes an RbNH-C(=NH)- group wherein
Rb is a hydrogen atom, a hydroxy, C1_9-alkoxycarbonyl,
cyclohexyloxycarbonyl, besnzyloxycarbonyl, benzoyl,
p-C1_3-alkyl-benzoyl or nicotinoyl group, whilst the
ethoxy moiety in the 2-position of the abovementioned
C1_g-alkoxycarbonyl group may additionally be
substituted by a methylsulfonyl or 2-ethoxy-ethyl
group,
Ar denotes a 1,4-phenylene group optionally substituted by
a methoxy group, or denotes a 2,5-thienylene group,
Het denotes a 1-methyl-2,5-be:nzimidazolylene,
2,5-benzothiazolylene, 1-methyl-2,5-indolylene or 1-methyl-
2,5-thieno[2,3-d]imidazolylene group and
Ra denotes an R2NR3- group wherein
R2 denotes a C1_3-alkyl group which may be substituted
by a carboxy, C1_6-alkylo:xycarbonyl, benzyloxycarbonyl,
methylsulfonylaminocarbonyl or 1H-tetrazol-5-yl group,
a C2_3-alkyl group substituted by a hydroxy, benzyloxy,
carboxy-C1_3-alkylamino, C1_3-alkoxycarbonyl-
C1_3-alkylamino, N-(C1_3-alkyl)-carboxy-C1_3-alkylamino
or N-(C1_3-alkyl)-C1_3-alkoxycarbonyl-C1_3-alkylamino
group, whilst in the abovE~mentioned groups the carbon
atom in the a-position to the adjacent nitrogen atom
may not be substituted, and
CA 02277949 1999-07-14
- :L7 -
R3 denotes a phenyl group optionally substituted by a
fluorine atom, or denotes a 2-pyridinyl group,
the tautomers, stereoisomers and the salts thereof.
The following are mentioned ass examples of particularly
preferred compounds:
(a) 2-[N-(4-amidinophenyl)-am:inomethyl]-benzthiazole-
5-carboxylic acid-N-phenyl-N-(2-carboxyethyl)-amide,
(b) 2- [N- (4-midinophenyl) -N-methyl-aminomethyl] -
benzthiazol-5-yl-carboxylic acid-N-phenyl-N-(2-
hydroxycarbonylethyl)-amide,
(c) 1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -
benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-
hydroxycarbonylethyl)-amide,
(d) 1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -
benzimidazol-5-yl-carboxylic acid-N-phenyl-
N-(3-hydroxycarbonylpropyl)-amide,
(e) 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-
benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-
N-(hydroxycarbonylmethyl)-amide,
(f) 1-Methyl-2-[2-(2-amidinothiophen-5-yl)ethyl]-
benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-
hydroxycarbonylethyl)-amide,
(g) 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-
benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-
hydroxycarbonylethyl)-amide,
CA 02277949 1999-07-14
- 18 -
(h) 1-Methyl-2- [2- (4-amidinophenyl) ethyl] -benzimidazol-5-
yl-carboxylic acid-N-(2-pyridyl)-N-(2-
hydroxycarbonylethyl)-amide,
(i) 1-Methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5
yl-carboxylic acid-N-phenyl-l~f-(2-hydroxycarbonylethyl)
amide,
(j) 1-Methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-
yl-carboxylic acid-N-phenyl-N-[2-(1H-tetrazol-5-yl)ethyl]-
amide, -
(k) 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-
benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[2-(1H-
tetrazol-5-yl)ethyl]-amide,
(1) 1-Methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-
benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-
hydroxycarbonylethyl)-amide,
(m) 1-Methyl-2- [N- (4-amidinophenyl) -N-methyl-aminomethyl] -
benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-
hydroxycarbonylethyl)-amide,
(n) 1-Methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-
benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-
hydroxycarbonylethyl)-amide,
(o) 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-
benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[(N-
hydroxycarbonylethyl-N-methyl)-2-aminoethyl]-amide,
(p) 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-
benzimidazol-5-yl-carboxylic acid-N-(3-fluorophenyl)-N-(2-
hydroxycarbonylethyl)-amide,
CA 02277949 1999-07-14
- 19 -
(q) 1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -
benzimidazol-5-yl-carboxylic acid-N-(4-fluorophenyl)-N-(2-
hydroxycarbonylethyl)-amide,
(r) 1-Methyl-2-[N-(4-amidino-2-methoxy-phenyl)-
aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-
(2-hydroxycarbonylethyl)-amide,
(s) 1-Methyl-2-[N-(4-amidino-2-methoxy-phenyl)-
aminomethyl)-benzimidazol-5-yl-carboxylic acid-N-(2-
pyridyl)-N-(2-hydroxycarbonylethyl)-amide,
(t) 1-Methyl-2-[N-(4-amidinophenyl)aminomethyl)-indol-5-yl-
carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide
and
(u) 1-Methyl-2- [N- (4-amidinophenyl) aminomethyl] -
thieno[2.3-d]imidazol-5-yl-carboxylic acid-N-phenyl-N-(2-
hydroxycarbonylethyl)-amide,
the tautomers, prodrugs, doub7_e prodrugs, stereoisomers and
the salts thereof.
The new compounds may be prepared by methods known per se,
for example by the following methods:
a. In order to prepare a compound of general formula I,
wherein E denotes an RbNH-C (=N13) - group, wherein Rb is a
hydrogen atom, a hydroxy or C1..3-alkyl group:
By reacting a compound of general formula
Ra - A - He t - B - Ar -~ C ( =NH ) - Z 1 , ( I I )
optionally formed in the reaction mixture,
CA 02277949 1999-07-14
- 20 -
wherein
A, B, Ar, Het and Ra are as lzereinbefore defined and
Z1 denotes an alkoxy or aralkoxy group such as the methoxy,
ethoxy, n-propoxy, isopropoxy or benzyloxy group or an
alkylthio or aralkylthio group such as the methylthio,
ethylthio, n-propylthio or benzylthio group, with an amine
of general formula
H2N - Rb~ ,(III)
wherein
''-' Rb ~ denotes a hydrogen atom or a hydroxy or Cl_3-alkyl
group.
The reaction is conveniently carried out in a solvent such
as methanol, ethanol, n-propanol, water, methanol/water,
tetrahydrofuran or dioxane at: temperatures between 0 and
150°C, preferably at temperatures between 20 and 120°C,
with a compound of general formula III or with a
corresponding acid addition salt such as ammonium
carbonate, for example.
A compound of general formula. II may be obtained, for
,... example, by reacting a compound of general formula I
wherein E denotes a cyano group, with a corresponding
alcohol such as methanol, ethanol, n-propanol, isopropanol
or benzyl alcohol in the presence of an acid such as
hydrochloric acid or by reacting a corresponding amide with
a trialkyloxonium salt such as triethyloxonium-
tetrafluoroborate in a solvent such as methylene chloride,
tetrahydrofuran or dioxane at temperatures between 0 and
50°C, but preferably at 20°C, or a corresponding nitrile
with hydrogen sulphide, appropriately in a solvent such as
pyridine or dimethylformamide and in the presence of a base
such as triethylamine and subsequent alkylation of the
resulting thioamide with a corresponding alkyl or aralkyl
halide.
CA 02277949 2006-02-17
27400-188(S)
- 21 -
b. In order~to prepare a compound of general formula I
wherein the Ra-A- group and E are as hereinbefore defined,
with the proviso that the R8-A- group contains a carboxy
group and E as hereinbefore defined or that the Ra-A- group
is as hereinbefore defined and E denotes an NHZ-C(=NH)-
group, or that the Ra=A- group contains a carboxy group and
E denotes an NHZ-C(=NH)- group:
Converting a compound of general formula
Ra' - A - Het - B - Ar - - E' , ( IV)
wherein
A, B, Ar and Het are as hereinbefore defined and
the Ra'-A- group and E' have the meanings given for the
Ra-A- group and E hereinbefore, with the proviso that the
Ra'-A- group contains a group which may be converted into a
carboxyl group by hydrolysis, treatment with an acid or
base, thermolysis or hydrogenolysis and E is as
hereinbefore defined or E' denotes a group which may be
converted into an NHZ-C(=NH)- group by~hydrolysis,
treatment with an acid or base, thermolysis or
hydrogenolysis and the Ra'-A- group has the meanings given
for the Ra-A- group hereinbefore or the Ra'-A- group
contains a group which may be converted into a carboxyl
group by hydrolysis, treatment with an acid or base,
thermolysis or hydrogenolysis and E' denotes a group which
may be converted into an NH2-C(=NH)- group by hydrolysis,
treatment with an acid or base, thermolysis or
hydrogenolysis,
is converted by hydrolysis, treatment with an acid or base,
thermolysis or hydrogenolysis into a compound of general
formula I, wherein the Ra-A- group and E are as
hereinbefore defined, with the proviso that the Ra-A- group
contains a carboxy group and E is as hereinbefore defined
or the Ra-A- group has the meanings given above and E
CA 02277949 1999-07-14
- 22 -
denotes an NHZ-C(=NH)- group or the Ra-A- group contains a
carboxy group and E denotes am NH2-C(=NH)- group.
Examples of groups which may be converted into a carboxy
group include a carboxyl group protected by a protecting
group and the functional derivatives thereof, e.g. the
unsubstituted or substituted amides, esters, thioesters,
trimethylsilylesters, orthoesters or iminoesters which may
conveniently be converted into a carboxyl group by
hydrolysis,
... the esters thereof with tertiary alcohols, e.g. the
tert.butylester, which are conveniently converted into a
carboxyl group by treatment with an acid or by thermolysis,
and
the esters thereof with aralkanols, e.g. the benzylester,
which are conveniently converted into a carboxyl group by
hydrogenolysis.
The hydrolysis is expediently carried out either in the
presence of an acid such as h:Ydrochloric acid, sulphuric
acid, phosphoric acid, acetic acid, trichloroacetic acid,
trifluoroacetic acid or mixtures thereof or in the presence
'""' 25 of a base such as lithium hydroxide, sodium hydroxide or
potassium hydroxide in a suitable solvent such as water,
water/methanol, water/ethanol" water/isopropanol, methanol,
ethanol, water/tetrahydrofuran or water/dioxane at
temperatures between -10 and L20°C, e.g. at temperatures
between room temperature and t:he boiling temperature of the
reaction mixture.
If the Re'-A- group and/or E' in a compound of formula IV
contains the tert.-butyl or te:rt.-butyloxycarbonyl group,
for example, these may also be: cleaved by treating with an
acid such as trifluoroacetic acid, formic acid, p-
toluenesulphonic acid, sulphuric acid, hydrochloric acid,
CA 02277949 1999-07-14
, ' - 23 -
phosphoric acid or polyphosphoric acid, optionally in an
inert solvent such as methylene chloride, chloroform,
benzene, toluene, diethylether, tetrahydrofuran or dioxane,
preferably at temperatures bEStween -10 and 120°C, e.g. at
temperatures between 0 and 60°C, or thermally optionally in
an inert solvent such as methylene chloride, chloroform,
benzene, toluene, tetrahydroi:uran or dioxane and preferably
in the presence of a catalytic quantity 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 40 and
120°C.
If the Ra'-A- group and/or E' in a compound of formula IV
contains the benzyloxy or ben.zyloxycarbonyl group, for
example, these may also be cleaved by hydrogenolysis 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°C, e.g. at room temperature, under a
hydrogen pressure of 1 to 5 bar.
c. In order to prepare a compound of general formula I
wherein the R8-A- group contains one of the ester groups
mentioned in the definition o:f the Ra-A- group
hereinbefore:
Reaction of a compound of general formula
Ra" - A - Het - B - Ar - E , (V)
wherein
B, E, Ar and Het are as hereinbefore defined and
the Ra"-A- group has the meanings given for the Ra-A- group
hereinbefore, with the proviso that the Ra"-A- group
CA 02277949 1999-07-14
- 24 -
contains a carboxyl group or a group which may be converted
into a corresponding ester group by means of an alcohol,
with an alcohol of general formula
HO - R~ ,(VI)
wherein
R, is the alkyl moiety of one of the above-mentioned groups
which may be cleaved in vivo, with the exception of the
R6-CO-O- (RSCR6) - group for a carboxyl group, or with the
formamide acetals thereof.
'"'~' or with a compound of general formula
Z2 - Rg . (VII) ..
wherein
RB denotes the alkyl moiety o:E one of the above-mentioned
groups which may be cleaved in vivo, with the exception of
the R6-CO-O- (RSCR6) - group for a carboxyl group and
Zz denotes a leaving group such as a halogen atom, e.g. a
chlorine or bromine atom.
The reaction with an alcohol of general formula VI is
.~-~ conveniently carried out in a solvent or mixture of
solvents such as methylene chloride, benzene, toluene,
chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or
dioxane, but preferably in an alcohol of general formula
VI, optionally in the presence of an acid such as
hydrochloric acid or in the presence of a dehydrating
agent, e.g. in the presence o:E isobutylchloroformate,
thionyl chloride, trimethylch:Lorosilane, hydrochloric acid,
sulphuric acid, methanesulphonic acid, p-toluenesulphonic
acid, phosphorus trichloride, phosphorus pentoxide, N,N'-
dicyclohexylcarbodiimide, N,N'-dicyclohexylcarbodiimide/N-
hydroxysuccinimide, N,N'-carbonyldiimidazole or N,N'-
thionyldiimidazole, triphenylphosphine/carbon tetrachloride
or triphenylphosphine/diethylazodicarboxylate, optionally
CA 02277949 2006-03-17
27400-188(S)
- 25 -
n the presence of a base such as potassium carbo~late, 1s~-
ethyl-diisopropylamine or N,N-dimethylamino-pyridine,
conveniently at temperatures between 0 and 150°C,
preferably at temperatures between 0 and 80°C.
R7ith a compound of general formula VII the reaction ~s
usefully carried out in a solvent such as meth~Tlene
chloride, tetrahydrofuran, dio~~ane, dimethylsulphoxide,
dimethylformamide or acetone, optionally in the presence of
a reaction accelerator such as sodium or potassium iodide
and preferably in the presence of a base such as sodium
carbonate or potassium carbonate or in the presence of a
tertiary organic base such as N-ethyl-diisopropylamine or
N-methyl-morpholine, which may act as solvent at the same
time, or optionally in the presence of silver carbonate or
silver oxide at temperatures between -30 and 100°C, but
preferably at temperatures between -10 and 80°C.
d. In order to prepare a compound of general formula I
wherein Rb denotes a group which may be cleaved in vivo:
Reacting a compound of general formula
Ra - A - Het - B - Ar - C(=NH) - NH2 ,(VIII)
LJhere 1n
Ra, A, Het , B and Ar are as hereini~efore def fined, wi th a
compound of general formula
3 D z3 - R5 , ( IX)
wherein
RS denotes a group which may be cleaved in Yi vo and
Z3 denotes a nucleofugic leaving group such as a halogen
atom, e.g. a chlorine, bromine or iodine atom.
CA 02277949 2006-03-03
27400-188(S)
- 26 -
The reaction is preferably carried out in a solvent such as
methanol, ethanol, methylene chloride, tetrahydrofuran,
toluene, dio}:ane, dimethylsulphoxide or dimethylformamide,
optionally in the presence of an inorganic or tertiary
organic base, preferably at temperatures between 20°C and
the boiling temperature of the solvent used.
With a compound of general formula IX, wherein Z3 denotes a
nucleofugic leaving group, the reaction is preferably
carried out in,'a solvent such as methylene chloride,
acetonitrile, tetrahydrofuran, toluene, dimethylfor-mamide
or dimethylsulphoxide, optionally in the presence of a base
such as sodium hydride, potassium carbonate, potassium
tart.-buto~:ide or N-ethyl-diisopropylamine at temperatures
between 0 and 60°C.
e_ In order to prepare a compound of general formula I
wherein B denotes an ethylene group, in which a methylene
group is replaced by a sulphinyl or sulphonyl group:
Oxidation of a compound of general formula
Ra - A - Het - B' - Ar - E , (X)
wherein
A, E, Ar, Het and Ra are as hereinbefore defined and
B' denotes an ethylene group, wherein a methylene group is
replaced by a sulphenyl or sulphinyl group.
The oxidation is preferably carried out in a solvent or
mixture of solvents, e.g. in water, water/pyridine,
acetone, methylene chloride, glacial acetic acid, glacial
acetic acid/acetic anhydride, dilute sulphuric acid or
trifluoroacetic acid, and depending on the o}>idising agent
used, at temperatures between -80 and 100°C.
CA 02277949 1999-07-14
- 27 -
In order to prepare a corresponding sulphinyl compound of
general formula I oxidation is conveniently carried out
with one equivalent of the oxidising agent used, e.g. with
hydrogen peroxide in glacial acetic acid, trifluoroacetic
acid or formic acid at 0 to 20°C or in acetone at 0 to
60°C, with a peracid such as performic acid in glacial
acetic acid or trifluoroacetic acid at 0 to 50°C or with m-
chloroperbenzoic acid in methylene chloride, chloroform or
dioxane at -20 to 80°C, with sodium metaperiodate in
aqueous methanol or ethanol at -15 to 25°C, with bromine in
glacial acetic acid or aqueous acetic acid, optionally in
the presence of a weak base such as sodium acetate, with N-
bromosuccinimide in ethanol, with tert.-butylhypochlorite
in methanol at -80 to -30°C, with iodobenzodichloride in
aqueous pyridine at 0 to 50°C, with nitric acid in glacial
acetic acid at 0 to 20°C, witra chromic acid in glacial
acetic acid or in acetone at 0 to 20°C and with sulphuryl
chloride in methylene chloride' at -70°C, the resulting
thioether chlorine complex is conveniently hydrolysed with
aqueous ethanol.
In order to prepare a sulphonyl compound of general formula
I, oxidation is carried out starting from a corresponding
sulphinyl compound, conveniently with one or more
equivalents of the oxidising agent used, or starting from a
corresponding sulphenyl compound, conveniently with two or
more equivalents of the oxidising agent used, e.g. with
hydrogen peroxide in glacial acetic acid/acetic anhydride,
trifluoroacetic acid or in formic acid at 20 to 100°C or in
acetone at 0 to 60°C, with a peracid such as performic acid
or with m-chloroperbenzoic acid in glacial acetic acid,
trifluoroacetic acid, methylene chloride or chloroform at
temperatures between 0 and 60°C, with nitric acid in
glacial acetic acid at 0 to 20°C, with chromic acid or
CA 02277949 1999-07-14
- 28 -
potassium permanganate in glacial acetic acid,
water/sulphuric acid or in acetone at 0 to 20°C. Thus, by
carrying out oxidation, for example, starting from a
corresponding sulphenyl compound, preferably in methylene
chloride, by treating with a corresponding amount of m-
chloroperbenzoic acid at temperatures between 20°C and the
reflux temperature of the reaction mixture, a corresonding
sulphonyl compound of genera7_ formula I is obtained which
may still contain a small amount of the corresponding
sulphinyl compound.
-.
f. In order to prepare a compound of general formula I
wherein E is a cyano group and B is an ethylene group in
which a methylene group linked either to group Het or to Ar
is replaced by an oxygen or sulphur atom or by a sulphinyl,
sulphonyl, carbonyl or -NR1- group:
Reacting a compound of general formula
Ra - A - Het - U , (XI)
with a compound of general formula
''~ V - Ar - C1V , (XI I )
wherein
R8, A, Ar and Het are as herei.nbefore defined,
one of the groups U or V denotes an HO-, HS-, HOSO-, HOSOZ-
or HNR1- group and the other group denotes a Z3CH2- group,
wherein R1 is as hereinbefore defined and Z3 denotes a
nucleofugic leaving group such as a halogen atom, e.g. a
chlorine, bromine or iodine atom.
The reaction is preferably carried out in a solvent such as
methanol, ethanol, methylene chloride, tetrahydrofuran,
toluene, dioxane, dimethylsulphoxide or dimethylformamide,
optionally in the presence of an inorganic or a tertiary
CA 02277949 1999-07-14
- 29 -
organic base, preferably at i:emperatures between 20°C and
the boiling temperature of the solvent used.
g. In order to prepare a compound of general formula I,
wherein E is a cyano group and Ra denotes an RZNR3- group:
Reacting a compound of generail formula
H - A - Het - B - Ar - CN , (XI I I )
wherein
A, B, Het and Ar are as hereinbefore defined, with an amine
of general formula
~R2
H - N , (XIV)
\R
3
wherein
RZ and R3 are as hereinbefore defined, or with the reactive
derivatives thereof.
The reaction of an acid of general formula XIII is
optionally carried out in a solvent or mixture of solvents
such as methylene chloride, d:imethylformamide, benzene,
toluene, chlorobenzene, tetrahydrofuran,
benzene/tetrahydrofuran or dioxane or in a corresponding
amine of general formula III, optionally in the presence of
a dehydrating agent, e.g. in t:he presence of isobutyl-
chloroformate, tetraethylorthocarbonate, trimethylortho-
acetate, 2,2-dimethoxypropane, tetramethoxysilane, thionyl
chloride, trimethylchlorosilane, phosphorus trichloride,
30- phosphorus pentoxide, N,N'-dic:yclohexylcarbodiimide, N,N'-
dicyclohexylcarbodiimide/N-hydroxysuccinimide, N,N'-
dicyclohexylcarbodiimide/1-hydroxy-benzotriazole, 2-(1H-
benzotriazol-1-yl)-1,1,3,3-tet:ramethyluronium-
tetrafluoroborate, 2-(1H-benzotriazol-1-yl)-1,1,3,3-
tetramethyluronium-tetrafluoroborate/1-hydroxy-
CA 02277949 1999-07-14
- 30 -
benzotriazole, N,N'-carbonyldiimidazole or
triphenylphosphine/carbon tetrachloride and optionally with
the addition of a base such ais pyridine, 4-dimethylamino-
pyridine, N-methyl-morpholine: or triethylamine,
conveniently at temperatures between 0 and 150°C,
preferably at temperatures between 0 and 100°C.
The reaction of a corresponding reactive compound of
general formula XIII such as the esters, imidazolides or
halides thereof with an amine of general formula XIV is
preferably carried out in a corresponding amine as solvent,
'"~ optionally in the presence of another solvent such as
methylene chloride or ether and preferably in the presence
of a tertiary organic base such as triethylamine, N-ethyl
diisopropylamine or N-methyl-morpholine at temperatures
between 0 and 150°C, preferab:Ly at temperatures between 50
and 100°C.
h. In order to prepare a benzimidazolyl, benzothiazolyl or
benzoxazolyl compound of general formula I wherein B
denotes an ethylene group:
Reacting a compound of genera:L formula
~2
Ra - A ~ . (XV)
wherein
Ra, A and Y are as hereinbefore defined, with a compound of
general formula
HO-CO - CH2CH2 - .Ar - E ,(XVI)
wherein
Ar and E are as hereinbefore defined, or with the reactive
derivatives thereof.
CA 02277949 1999-07-14
- 31 -
The reaction is conveniently carried out in a solvent or
mixture of solvents such as methylene chloride,
dimethylformamide, benzene, toluene, chlorobenzene,
tetrahydrofuran, benzene/tetrahydrofuran or dioxane,
optionally in the presence of a dehydrating agent, e.g. in
the presence of isobutylchloroformate, tetraethylortho-
carbonate, trimethylorthoacetate, 2,2-dimethoxypropane,
tetramethoxysilane, thionyl chloride, trimethylchloro-
silane, phosphorus trichloride, phosphorus pentoxide, N,N'-
dicyclohexylcarbodiimide, N,N'-dicyclohexylcarbodiimide/N-
,.~. hydroxysuccinimide, N,N'-dicyclohexylcarbodiimide/1-
hydroxy-benzotriazole, 2-(1H-:benzotriazol-1-yl)-1,1,3,3-
tetramethyluronium-tetrafluoroborate, 2-(1H-benzotriazol-1-
yl)-1,1,3,3-tetramethyluronium tetrafluoroborate/1-hydroxy-
benzotriazole, N,N'-carbonyld:iimidazole or triphenyl-
phosphine/carbon tetrachloride, and optionally with the
addition of a base such as pyridine, 4-dimethylamino-
pyridine, N-methyl-morpholine or triethylamine,
appropriately at temperatures between 0 and 150°C,
preferably at temperatures between 0 and 100°C.
The reaction of a corresponding reactive compound of
general formula XVI such as the esters, imidazolides or
halides thereof with an amine of general formula XV is
preferably carried out in a solvent such as methylene
chloride, ether or tetrahydrofuran and preferably in the
presence of a tertiary organic' base such as triethylamine,
N-ethyl-diisopropylamine or N-methyl-morpholine, which may
simultaneously be used as solvents, at temperatures between
0 and 150°C, preferably at temperatures between 50 and
100°C.
i. In order to prepare a quinoxalin-2-one compound of the
general formula:
CA 02277949 1999-07-14
- 32 -
Reacting a compound of general formula
~2
Ra A ( , (XVI I )
NR1H
wherein
Ra, R1 and A are as hereinbefore defined, with a compound
of general formula
HO-CO - COCH2 - i~r - E , (XVI II )
wherein
Ar and E are as hereinbefore defined, or with the reactive
derivatives thereof.
The reaction is conveniently carried out in a solvent or
mixture of solvents such as nnethylene chloride,
dimethylformamide, benzene, toluene, chlorobenzene,
tetrahydrofuran, benzene/tetrahydrofuran, ethanol or
dioxan, optionally in the preaence of a dehydrating agent,
e.g. in the presence of isobutyl chloroformate, tetraethyl
orthocarbonate, trimethyl ort:hoacetate,
2,2-dimethoxypropane, tetrameahoxysilane, thionyl chloride,
"., trimethylchlorosilane, phosphorus trichloride, phosphorus
pentoxide, N,N'-dicyclohexylcarbodiimide,
N,N'-dicyclohexylcarbodiimide:/N-hydroxysuccinimide,
N,N'-dicyclohexylcarbodiimide/1-hydroxy-benzotriazole,
2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-
tetrafluoroborate, 2-(1H-benzotriazol-1-yl)-1,1,3,3-
tetramethyluronium-tetrafluoroborate/1-hydroxy-
benzotriazole, N,N'-carbonyldiimidazole or
triphenylphosphine/carbon tetrachloride, and optionally
with the addition of a base such as pyridine,
4-dimethylaminopyridine, N-methyl-morpholine or
triethylamine, appropriately at temperatures of between 0
and 150°C, preferably at temperatures of between 0 and
100°C.
CA 02277949 1999-07-14
- :33 -
However, it is particularly preferred to carry out the
reaction with a corresponding reactive compound of general
formula XVIII such as the esters, imidazolides or halides
thereof with an amine of general formula XVII in a solvent
such as methylene chloride, ether, ethanol or
tetrahydrofuran and optionally in the presence of a
tertiary organic base such as triethylamine, N-ethyl-
diisopropylamine or N-methyl-onorpholine, which may
simultaneously serve as solvent, at temperatures of between
0 and 150°C, preferably at temperatures of between 50 and
,.-. 100°C.
j. In order to prepare a compound of general formula I
wherein R2 denotes a C1_4-alk~rl group substituted by an
alkylsulphonylaminocarbonyl group:
Reacting a compound of genera7_ formula
R '
2
N - A - Het - B - Ar - E , ( IXX)
R3
wherein
R3, A, B, E, and Het are as he:reinbefore defined and
R2' denotes a C1-4-alkyl group substituted by a carboxy
group, or the reactive derivatives thereof, with a salt of
a compound of general formula
Cl_3-Alkyl-S02-NH2 (XX) .
The reaction is preferably carried out with a corresponding
reactive compound of general formula IXX such as the
esters, imidazolides or halides thereof with a salt of a
compound of general formula XX, preferably with an alkali
metal salt thereof such as a stadium salt, in a solvent such
as methylene chloride, ether, ethanol, tetrahydrofuran or
CA 02277949 1999-07-14
- 34 -
dimethylformamide at temperatures between 0 and 150°C,
preferably at temperatures of: between 50 and 100°C.
In the reactions described he:reinbefore, any reactive
groups present such as hydroxy, carboxy, amino, alkylamino
or imino groups may be protected during the reaction by
means of conventional protecting groups which are removed
by cleaving after the reaction.
For example, the protecting group for a hydroxy group may
be the trimethxlsilyl, acetyl, benzoyl, tert.butyl, trityl,
-- benzyl or tetrahydropyranyl group,
the protecting group for a carboxyl group may be the
trimethylsilyl, methyl, ethyl, tert.butyl, benzyl or
tetrahydropyranyl group, and
the protecting group for an amino, alkylamino or imino
group may be the acetyl, trif:Luoroacetyl, benzoyl,
ethoxycarbonyl, tert.-butoxycarbonyl, benzyloxycarbonyl,
benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group and for
the amino group the phthalyl group may also be considered.
The optional subsequent cleaving of a protecting group may,
for example, be carried out hydrolytically in an aqueous
solvent, e.g. in water, isopropanol/water, tetrahydro-
furan/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 100°C,
preferably at temperatures between 10 and 50°C.
However, a benzyl, methoxybenzyl or benzyloxycarbonyl group
may for example be cleaved hydrogenolytically, e.g. using
hydrogen in the presence of a catalyst such as
CA 02277949 1999-07-14
- 35 -
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 50°C, but preferably at room temperature, under a
hydrogen pressure of 1 to 7 b,ar, 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 50°C, but
'"' preferably at room temperature.
However, a 2,4-dimethoxybenzy:l group is preferably cleaved
in trifluoroacetic acid in the presence of anisole.
A tert.butyl or tert.butyloxycarbonyl group is preferably
cleaved by treatment with an acid such as trifluoroacetic
acid or hydrochloric acid, optionally using a solvent such
as methylene chloride, dioxane~, or ether.
A phthalyl group is preferably cleaved in the presence of
hydrazine or a primary amine :such as methylamine,
ethylamine or n-butylamine in a solvent such as methanol,
.-.
ethanol, isopropanol, toluenefwater or dioxane, at
temperatures between 20 and 5G°C.
An allyloxycarbonyl group is cleaved by treating with a
catalytic amount of tetrakis-(triphenylphosphine)-
palladium(O), 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 100°C, preferably at room
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-
CA 02277949 1999-07-14
~ - 36 -
diazabicyclo[2.2.2)octane, a.t temperatures between 20 and
70°C.
The compounds of general formulae II to XX used as starting
materials, some of which are known from the literature, may
be obtained by methods known from the literature and
moreover their production is described in the Examples.
Thus, for example, a compound of general formula II is
obtained by reacting a corresponding nitrile which in turn
is convenientl~r obtained by processes f to h, with a
~-~ corresponding thio or alcohol in the presence of hydrogen
chloride or bromide.
A compound of general formulae IV, V, VIII, X and IXX used
as starting material is conveniently obtained according to
a process of the present invention.
A starting compound of general formula XI in which U
denotes a halomethyl group i:~ conveniently obtained by
cyclisation of a corresponding ester which is substituted
in the o-position by a suitable halogen atom and a
methoxyacetamido group, to farm a corresponding bicyclic 2-
alkoxymethyl compound, optionally subsequent hydrolysis and
optionally subsequent amidation of a resulting carboxylic
acid with a corresponding amine, converting the
alkoxymethyl compound thus obtained into the corresponding
halomethyl compound, which can if necessary be subsequently
converted into the desired compound by means of a suitable
compound. If the cyclisation is carried out with a
suitable carbonic acid derivative, a starting compound of
general formula XI is obtained wherein U denotes a hydroxy,
mercapto or amino group.
A starting compound of general formula XIII is obtained by
cyclisation of a corresponding o-disubstituted ester,
followed by saponification of the resulting ester and
CA 02277949 1999-07-14
_ 37 _
subsequent amidation of the carboxylic acid thus obtained
with a corresponding amine.
Furthermore, an imidazopyridi.ne substituted in the 5-
position by a methyl group and obtained by cyclisation can
be converted, via the corresponding N-oxide, into the
corresponding hydroxymethyl compound which is converted by
oxidation into the desired carboxylic acid of general
formula XIII.
The compounds of general formulae III, VI, VII, IX and XII
-- used as starting materials are obtained by conventional
methods, for example by reducing an aromatic ester
substituted in the o-position by an optionally substituted
amino group and a nitro group, and optionally subsequent
cyclisation of the resulting o-diamino compound with a
corresponding carboxylic acid.
Furthermore, the compounds of general formula I obtained
may be separated into their enantiomers and/or
diastereomers.
Thus, for example, the compounds of general formula I
obtained which occur in racemate form may be separated by
"~ 25 methods known per 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
general formula I having at least 2 asymmetric carbon atoms
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.
The separation of enantiomers is preferably effected by
column separation on chiral pr~ases or by recrystallisation
CA 02277949 1999-07-14
- 38 -
from an optically active solvent or by reacting with an
optically active substance, e=specially acids and the
activated derivatives thereof= or alcohols, which forms
salts or derivatives such as e.g. esters or amides with the
racemic compound, and separation of the diastereomeric salt
mixture 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 are, 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 and
quinaldic 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 of
suitable acids include for example hydrochloric acid,
hydrobromic acid, sulphuric acid, phosphoric acid, fumaric
acid, succinic acid, lactic acid, citric acid, tartaric
acid or malefic 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 salts thereof with inorganic
or organic bases, more particularly, for pharmaceutical
use, into the physiologically acceptable salts thereof.
Examples of suitable bases include for example sodium
hydroxide, potassium hydroxide, cyclohexylamine,
ethanolamine, diethanolamine .and triethanolamine.
CA 02277949 1999-07-14
- 39 -
As already mentioned, the new compounds of general formula
I and the salts thereof have valuable properties. Thus,
the compounds of general forcr~ula I wherein E denotes a
cyano group are valuable intermediate products for
preparing the other compounds of general formula I and the
compounds of general formula I wherein E denotes an
RbNH-C(=NH)- group and the tautomers, the stereoisomers and
the physiologically acceptable salts thereof have valuable
pharmacological properties, particularly a thrombin-
inhibiting effect, an effect of prolonging the thrombin
time and an inhibitory effect on related serine proteases
",~ such as e.g. trypsin, urokinase factor VIIa, factor Xa,
factor IX, factor XI and factor XII, whilst a few compounds
such as for example the compound of Example 16
simultaneously also have a slight inhibitory effect on
thrombocyte aggregation.
For example, the following compounds:
A = 2-[N-(4-amidinophenyl)-aminomethyl]-benzthiazole-
5-carboxylic acid-N-phenyl-N-(2-carboxyethyl)-amide,
B = 1-methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol
5-yl-carboxylic acid-N-phenyl-N-(3-hydroxycarbonyl
propyl)-amide,
C = 1-methyl-2-[(4-amidinophenyl)oxymethyl]-benzimidazol-
5-yl-carboxylic acid -N-F~henyl-N-(hydroxycarbonyl-
methyl)-amide,
D = 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-
benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-
hydroxycarbonylethyl)-amide,
E = 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-
benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-
N-(hydroxycarbonylmethyl)-amide,
CA 02277949 2005-06-O1
27400-188(S)
- 40 -
F = 1-methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-
yl-carboxylic acid-N-phenyl-N-[2-(1H-tetrazol-5-
yl)ethyl]-amide and
G = 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-
benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-
hydroxycarbonylethyl)-amide
were investigated as follows for their effects on thrombin
time:
Materials: plasma, from human citrated blood.
Test thrombin (bovine), 30U/ml, Behring Werke,
Marburg
Diethylbarbiturate acetate buffer, ORWH 60/61,
Behring Werke, Marburg
TM
Biomatic B10 coagulometer, Sarstedt
Method:
The thrombin time was determined using a Biomatic B10
coagulometer made by Messrs. Sarstedt.
As the test substance, 0.1 ml of human citrated plasma and
0.1 ml diethylbarbiturate buffer (DBA buffer) were added to
the test strip prescribed by the manufacturer. The mixture
was incubated for one minute at 37°C. The clotting
reaction was started by the addition of 0.3 U test thrombin
in 0.1 ml DBA buffer. The time is measured using the
apparatus from the addition of the thrombin up to the
cloy ting of the mixture. Mixtures to which o.1 ml of DBA
buffer were added were used as the controls.
According to the definition, a dosage-activity curve was
used to determine the effective concentration of the
CA 02277949 1999-07-14
- 41 -
substance, i.e. the concentration at which the thrombin
time is double compared with the control.
The Table which follows contains the results found:
Substance Thrombin time
(ED200 in ~M)
0.04
B 0.06
C 0.15
D 0.03
'~ E 0.09
0.03
G 0.03
By way of example, no acute toxic side effects were
observed when compounds A, D, E and G were administered to
rats in doses of up to 10 mg/k:g i.v. The compounds are thus
well tolerated.
In view of their pharmacological properties the new
compounds and the physiologically acceptable salts thereof
are suitable for the prevention and treatment of venous and
arterial thrombotic diseases, such as for example the
treatment of deep leg vein thrombosis, for preventing
reocclusions after bypass operations or angioplasty
(PT(C)A), and occlusion in peripheral arterial diseases
such as pulmonary embolism, disseminated intravascular
coagulation, for preventing coronary thrombosis, stroke and
the occlusion of shunts or stents. In addition, the
compounds according to the invention are suitable for
antithrombotic support in thrombolytic treatment, such as
for example with rt-PA or streptokinase, for preventing
long-term restenosis after PT(C')A, for preventing
metastasis and the growth of clot-dependent tumours and
fibrin-dependent inflammatory processes.
CA 02277949 1999-07-14
- 42 -
The dosage required to achieve such an effect is
appropriately 0.1 to 30 mg/kg, preferably 0.3 to 10 mg/kg
by intravenous route, and 0.1 to 50 mg/kg, preferably 0.3
to 30 mg/kg by oral route, in each case administered 1 to 4
times a day. For this purpose, the compounds of formula I
prepared according to the invention may be formulated,
optionally together with other active substances, with one
or more inert conventional carriers and/or diluents, e.g.
with corn starch, lactose, glucose, microcrystalline
l0 cellulose, magnesium stearate, polyvinylpyrrolidone, citric
acid, tartaric,~acid, water, water/ethanol, water/glycerol,
.-- water/sorbitol, water/polyethyleneglycol, propyleneglycol,
cetylstearyl alcohol, carbox;rmethylcellulose or fatty
substances such as hard fat or suitable mixtures thereof,
to produce conventional galenic preparations such as plain
or coated tablets, capsules, powders, suspensions or
suppositories.
The Examples which follow are: intended to illustrate the
invention:
CA 02277949 1999-07-14
- ~4 3 -
Preliminary remarks
Unless otherwise specified, the Rf values were always
determined using polygram silica gel plates produced by
Messrs. E. Merck of Darmstadt.
The EKA mass spectra (electrospray mass spectra of cations)
are described, for example, in ~~Chemie unserer Zeit 6,
308-316 (1991) .
Example 1
3-Methyl-2- (2- (4-amidinopheny:L) ethyl] -imidazo [4, 5-b] -
pyridine-6-carboxylic acid -N~-phenyl-N-(2-
ethoxycarbonylethyl)-amide
a) Methyl 6-methylamino-5-nitr_o-nicotinate
1.6 g (7.4 mMol) of methyl 6-c:hloro-5-vitro-nicotinate (see
Bernie et al. in J. Chem. Soc.. 1951, 2590) were stirred in
20 ml of 40% aqueous methylamine solution at room
temperature for 30 minutes. The reaction mixture was then
diluted with ice water, the yellow precipitate formed was
filtered off and dried.
Yield: 1.2 g (80 % of theory),
.-- 25 Rf value: 0.66 (silica gel; ethyl acetate/ethanol/glacial
acetic acid = 90:5:5)
b) Methyl 5-amino-6-methylamino-nicotinate
To a solution of 3.1 g (15 mMol) of methyl 6-methylamino-
5-vitro-nicotinate in 100 ml of ethanol/dichloromethane
(3:1) was added 1 g of palladium on charcoal (10%) and the
resulting suspension was hydrogenated at. room temperature
under 5 bar of hydrogen pressure for 1.5 hours. The
catalyst was then filtered off and the solvent was
distilled off in vacuo. The crude oily product obtained
was further reacted directly.
Yield: 2.4 g (92 % of theory),
CA 02277949 1999-07-14
' - 44 -
Rf value: 0.44 (silica gel; ethyl acetate/ethanol/ammonia =
90:10:1)
c) Methyl 5-f2-(4-cyanophenvl~ethylcarbonvlaminol-
6-methvlamino-nicotinate
A solution of 2.6 g (15 mMol) of 3-(4-cyanophenyl)propionic
acid in 25 ml of absolute tetrahydrofuran was mixed with
2.4 g (15 mMol) of N,N'-carbonyldiimidazole and stirred for
20 minutes at room temperature. Then the imidazolide was
mixed with a solution of 2.3 g (13 mMol) of methyl 5-amino-
6-methylamino-nicotinate in :..>5 ml of dimethylformamide and
.-..
heated for 3 hours to 100°C. After the removal of the
solvent in vacuo the crude product obtained was taken up in
ethyl acetate, the organic phase was washed with water and
after drying over sodium sulphate it was again freed from
solvent. The residue obtained was purified by flash
chromatography (silica gel; gradient: dichloromethane to
dichloromethane/ethanol = 19:1).
Yield: 2.1 g (50 0 of theory) of beige solid
Rf value: 0.54 (silica gel; ethyl acetate/ethanol/ammonia =
90:10:1)
d) Methylyl 3-methyl-2- 2-(4-cvanophenvl)ethyl
imidazo f4 5-blp~~ridine-6-carboxyl ate
A solution of 2 . 0 g (5 . 9 mMol l of methyl 5- [2- (4-
cyanophenyl)ethylcarbonylamino]-6-methylamino-nicotinate in
50 ml glacial acetic acid was heated to 100°C for one hour.
After removal of the solvent t:he residue was taken up in
dichloromethane, washed with rhodium hydrogen carbonate
solution, dried with sodium sulphate and the solvent was
distilled off again.
Yield: 1.7 g brown solid (89 ~c of theory),
Rf value: 0.50 (silica gel; ethyl acetate/ethanol/ammonia =
90:10:1)
CA 02277949 1999-07-14
- 45 -
e) 3-Methyl-2- f2- (4-cvanophenyl) ethvll
imidazof4,5-b]pvridine-6-carboxylic acid
A solution of 3 .2 g (10 mMol;l of methyl 3-methyl-2- [2- (4-
cyanophenyl)ethyl]-imidazo[4.5-b]pyridine-6-carboxylate in
150 ml methanol was mixed with a solution of 1.5 g lithium
hydroxide in 20 ml water and stirred for 24 hours at room
temperature. Then the mixture was diluted with 50 ml of
water, the alcohol was disti7.led off and the aqueous phase
was washed with ethyl acetate:. After acidification with
dilute hydrochloric acid the mixture was extracted several
times with dichloromethane/me~thanol (9:1), the organic
"~. phase was dried with sodium ~;ulphate and the solvent was
distilled off.
Yield: 2.1 g beige solid (70 °s of theory),
Rf value: 0.38 (silica gel; ethyl acetate/ethanol/ammonia
- 50:45:5)
f) 3-Methyl-2-f2-(4-cyanophenyl)ethyl]-imidazof4 5-bl-
pvridine-6-carboxylic acid-N-phenyl-N-(2-ethoxvcarbonvl-
ethyl)-amide
A solution of 2.0 g (6.5 mMo1) of 3-methyl-2-[2-
(4-cyanophenyl)ethyl]-imidazo[4,5-b]pyridine-6-carboxylic
acid in 100 ml dichloromethane was mixed with 20 ml thionyl
chloride and refluxed for 2 hours. After the liquid
components had been distilled off the crude product was
taken up twice more in dichloromethane and the solvent was
distilled off each time. The crude acid chloride thus
obtained (2 g) was suspended in 100 ml of tetrahydrofuran
and mixed with 1.2 g (6.5 mMo~.) of N-(2-ethoxycarbonyl-
ethyl)aniline. Then within 5 minutes 0.73 g (7.2 mMol) of
triethylamine were added dropwise. After 1 hour's stirring
the solvent was distilled off in vacuo, the residue was
taken up in ethyl acetate, the' organic phase was washed
with water and dried with sodium sulphate. After
distillation of the solvent and flash chromatography
(silica gel; dichloromethane t.o dichloromethane/ethanol =
49:1) the desired compound was isolated as a brownish oil.
CA 02277949 1999-07-14
- 46 -
Yield: 1.9 g (65 % of theory),
Rf value: 0.44 (silica gel; ~'thyl acetate/ethanol/ammonia =
90:10:1)
g) 3-Methyl-2-f2-l4-amidinophenvl)ethvll-imidazof4 5-bl-
pvridine-6-carboxylic acid-N-phenyl-N-(2-
ethoxvcarbonyleth~rl)-amide
1.8 g (3.7 mMol) of 3-methyl-2-[2-(4-cyanophenyl)ethyl]-
imidazo[4,5-b]pyridine-6-carboxylic acid-N-phenyl-N-(2-
ethoxycarbonylethyl)-amide were stirred into 100 1 of
ethanol saturated with hydrogen chloride for 16 hours first
at 0°C and then at room temperature until no more starting
r.
material could be detected by thin layer chromatography.
Then the solvent was distillESd off, the oily residue was
taken up in 50 ml of absolutE~ ethanol and mixed with 3.6 g
(37 mMol) of ammonium carbonate. After 4 hours the solvent
was distilled off in vacuo, t:he crude product obtained was
purified by flash chromatography (silica gel; gradient:
dichloromethane/ethanol 19:1 to 4:1) and evaporated down
again.
Yield: 1.6 g of beige solid (80 % of theory),
Rf value: 0.30 (silica gel; ethyl acetate/ethanol/ammonia =
90:5:5)
Example 2
3-Methyl-2- [2- (4-amidinophenyl) ethyl] -imidazo [4, 5-b] -
pyridine-6-carboxylic acid-N-phenyl-N-(2-
hydroxycarbonylethyl)-amide
A solution of 535 mg (1.0 mMol) of 3-methyl-2-[2-(4-
amidinophenyl)ethyl]-imidazo[4,5-b]pyridine-6-carboxylic
acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide in 10 ml
ethanol was mixed with 5 ml of 2N sodium hydroxide solution
and stirred for 2 hours at room temperature. Then the
mixture was diluted with 10 m:1 water, the alcohol was
distilled off, the aqueous phase was washed with 20 ml
CA 02277949 1999-07-14
, ' _ 47 -
ethyl acetate and acidified with concentrated hydrochloric
acid, whereupon the desired compound was precipitated in
the form of white crystals.
Yield: 375 mg (74 % of theory),
Rf value: 0.23 (silica gel; ethyl acetate/ethanol/ammonia =
90:5:5)
C26H26N6~3 (470.54)
Mass spectrum: (M+H)+ = 471
Example 3
""""' 3-Methyl-2- [2- (4-amidinopheny.l) ethyl] -imidazo [4, 5-
b]pyridin-6-yl-carboxylic acid-N- (2-pyridyl) -N- (2-
methoxycarbonylethyl)-amide-hydrochloride
Prepared analogously to Example 1 from 3-methyl-2-[2-(4-
cyanophenyl) ethyl] -imidazo [4, 5-b] pyridin-6-yl-carboxylic
acid-N- (2-pyridyl) -N- (2-metho:~cycarbonylethyl) -amide,
methanolic hydrochloric acid, methanol and ammonium
carbonate.
Yield: 75 % of theory,
C26H27N7~3 (485.55)
Rf value: 0.31 (silica gel; ethyl acetate/ethanol/ammonia
50:45:5)
EKA mass spectrum: (M+H)+ = 486
Example 4
3-Methyl-2-[2-(4-amidinophenyl)ethyl]-imidazo[4,5-
b]pyridin-6-yl-carboxylic acif.-N-phenyl-N-
ethoxycarbonylmethyl-amide-hydrochloride
Prepared analogously to Example 1 from 3-methyl-2-[2-(4-
cyanophenyl)ethyl]-imidazo[4,5-b]pyridin-6-yl-carboxylic
acid-N-phenyl-N-ethoxycarbonylmethyl-amide, ethanolic
hydrochloric acid, ethanol and ammonium carbonate.
CA 02277949 1999-07-14
- 48 -
Yield: 84 % of theory,
C27H28N603 (484.56)
Rf value: 0.44 (silica gel; a_thyl acetate/ethanol/ammonia
- 50:45:5)
EKA mass spectrum: (M+H)+ = 485
Example 5
3-Methyl-2- [2- (4-amidinophenyl) ethyl] -imidazo [4, 5-
b]pyridin-6-yl-carboxylic acid-N-phenyl-N-
hydroxycarbonylmethyl-amide-:hydrochloride
Prepared analogously to Example 2 from 3-methyl-2-[2-(4-
amidinophenyl)ethyl]-imidazo[4,5-b]pyridin-6-yl-carboxylic
acid-N-phenyl-N-ethoxycarbom,rlmethyl-amide-hydrochloride
and sodium hydroxide solution.
Yield: 85 % of theory,
C25H24N6~3 (456.51)
Rf value: 0.19 (silica gel; ethyl acetate/ethanol/ammonia
- 50:45:5)
EKA mass spectrum: (M+H) + = 9:57
Example 6
2-[2-(4-amidinophenyl)ethyl]-3-methyl-6-(2-methoxycarbonyl-
2,3-dihydroindol-1-yl-carbonyl)-imidazo[4,5-b)pyridine-
hydrochloride
Prepared analogously to Example 1 from 2-[2-(4-
cyanophenyl)ethyl]-3-methyl-6-(2-methoxycarbonyl-
2,3-dihydroindol-1-yl-carbonyl)-imidazo[4,5-b]pyridine,
methanolic hydrochloric acid, methanol and ammonium
carbonate.
Yield: 20 % of theory,
C27H26N603 (482.54)
Rf value: 0.30 (silica gel; ethyl acetate/ethanol/ammonia
CA 02277949 1999-07-14
- ~49 -
- 50:45:5)
EKA mass spectrum: (M+H)+ = 483
Example 7
2-[2-(4-amidinophenyl)ethyl]-3-methyl-6-(2-carboxy-
2,3-dihydroindol-1-yl-carbonyl)-imidazo[4,5-b]pyridine-
hydrochloride
Prepared analogously to Example 2 from 2-[2-(4-
amidinophenyl)ethyl]-3-methyl-6-(2-methoxycarbonyl-
2,3-dihydroindol-1-yl-carbony:L)-imidazo[4,5-b]pyridine-
hydrochloride and sodium hydroxide solution.
Yield: 90 % of theory,
C26H24N6~3 (468.52)
Rf value: 0.24 (silica gel; ethyl acetate/ethanol/ammonia
- 50:45:5)
EKA mass spectrum: (M+H)+ - x:69
( M+Na ) + = 9: 91
Example 8
1-Methyl-2-[(4-amidinophenyl)oxymethyl]-
"... imidazo[4,5-b]pyridin-5-yl-carboxylic acid-N-(2-pyridyl)-N-
(2-ethoxycarbonylethyl)-amide
a) 2-Amino-3-methylamino-6-methyl-pyridine
8.35 g (50 mMol) of 2-Methyl-5-methylamino-6-nitro-pyridine
(Heterocycles 38, 529 (1994)) were dissolved in 300 1 ethyl
acetate and hydrogenated with 1.5 g Raney nickel for 3.5
hours at room temperature. Then the catalyst was filtered
off and the filtrate was evaporated down. After
crystallisation of the result ing residue from petroleum
ether, 5.75 g (84 % of theory) were obtained as olive-green
crystals.
C7H11N3 (137.20)
CA 02277949 1999-07-14
- 50 -
Melting point: 112-113°C
b) 1.5-Dimethvl-2-f(4-cvanophenyl)oxymethvll
imidazof4,5-bl-pyridine
11.4 g (63 mMol) of 4-cyano-;phenoxyacetic acid were
dissolved in 200 ml of absolute tetrahydrofuran and mixed
at room temperature with 10.:2 g (63 mMol) of
N,N'-carbonyldiimidazole. After 15 minutes at 60°C, 5.70 g
(41.5 mMol) of 2-amino-3-metlzylamino-6-methyl-pyridine were
added. After 2 hours at 60°C the solvent was distilled off
and the crystalline residue was mixed with water, washed
with water and~dried. After crystallisation from ethanol
9.95 g (91 % of theory) were obtained in the form of white
crystals.
C16H14N40 (278.32)
Mass spectrum: M+ = 278
c) 1, 5-Dimethyl-2- f (4-cyanophenvl) oxvmeth~rll -
imidazo 4,5-blgyridin-4-N-oxide
2.62 g (10 mMol) of 1,5-dimethyl-2-[(4-cyanophenyl)-
oxymethyl]-imidazo[4,5-b]pyridine were suspended in 125 ml
dichloromethane and mixed with 2.62 g (12.7 mMol) of
m-chloroperbenzoic acid, whereupon a clear solution was
obtained. After 2 hours at room temperature the solvent
"~' 25 was distilled off and the residue obtained was mixed with a
sodium hydrogen carbonate solution. After 30 minutes the
white crystalline product obtained was suction filtered,
washed with water and dried a~~ 40°C.
Yield: 2.45 g (83 % of theory;l,
C16H14N402 (294.30)
Mass spectrum: M+ - 294
d) 1-Methyl-2-f(4-cyano~henyl)oxymethyll-5-hvdroxvmethvl-
imidazof4,5-blpyridine
2.40 g (8.2 mMol) of 1,5-dimet:hyl-2-[(4-cyanophenyl)-
oxymethyl]-imidazo[4,5-b]pyridin-4-N-oxide were suspended
in 75 ml dichloromethane and mixed with 2.4 ml of
CA 02277949 1999-07-14
- 51 -
trifluoroacetic acid anhydride (16.9 mMol), whereupon a
clear solution was obtained. After 16 hours at room
temperature the solvent was distilled off, the viscous
residue obtained was taken up in 50 ml dichloromethane and
covered with 50 ml of 2M sodium hydrogen carbonate
solution. After 3 hours' vigorous stirring the precipitate
formed was suction filtered, washed with water and dried at
40°C.
Yield: 1.85 g white powder (78 % of theory),
C16H14N402 (294.30)
Melting point: 172°C
e) 1-Methyl-2-f(4-cvanophenyl)oxvmethyll-imidazo 4 5-bl-
pyridine-5-carbaldehyde
3.65 g (12.5 mMol) of 1-methyl-2-[(4-cyanophenyl)-
oxymethyl]-5-hydroxymethyl-imidazo[4,5-b]pyridine were
dissolved in 500 ml dichloromethane and mixed with 15.0 g
of manganese dioxide. After :~6 hours at room temperature
the mixture was filtered through kieselgur and the solvent
was distilled off. The filtrate obtained was evaporated
down, the crystalline precipit=ate was triturated with
ether, suction filtered and dried.
Yield: 3.05 g white powder (8~6 % of theory),
C16H12N4~2 (292.30)
Melting point: 231-234°C
f) 1-Methyl-2-f(4-cyanophenyl)oxvmethyll-5-carboxy-imidazo-
[4 . 5-b~ pvridine
1 .25 g (4.3 mMol) of 1-methyl-2- [ (4-cyanophenyl) oxymethyl] -
imidazo[4,5-b]pyridine-5-carba.ldehyde were dissolved in 10
ml formic acid and mixed at 0°C with 1.0 ml hydrogen
peroxide (33% strength). After 12 hours at 4°C the white
precipitate formed was suction filtered, washed with water
and dried at 40°C.
Yield: 0.81 g (61 % of theory) ,
C16H12N4~3 (308.7)
CA 02277949 1999-07-14
' , - 52 -
g) 1-Methyl-2-f(4-cyanophenyl)oxymethyll-
imidazof4 5-blpyridin-5-yl-c:arboxylic acid-N-(2-pyridyl)-N-
(2-methoxycarbonvlethyl)-amide
308 mg (1.0 mMol) of 1-methyl-2-[(4-cyanophenyl)oxymethyl]-
5-carboxy-imidazo(4.5-b]pyri.dine were suspended in 5 ml of
dimethylformamide and mixed with 303 mg (3.0 mMol) of
N-methyl-morpholine and 321 mg (1.0 mMol) of
O-(benzotriazol-1-yl)-N,N,N~,N~-tetramethyl-uronium
tetrafluoroborate. After 10 minutes at room temperature a
solution of 215 mg (1.2 mMol) of methyl N-(2-pyridyl)-
3-amino-propionate in 2 ml of dimethylformamide was added,
,.... whereupon a clear solution was obtained. After 12 hours at
room temperature the reaction solution was stirred into
ice-water. After extracting 3 times with ethyl acetate the
combined organic extracts were washed with a saline
solution, dried over sodium aulphate and evaporated down.
The residue obtained was chromatographed on silica gel with
dichloromethane/ethanol (90::1 to 25:1).
Yield: 165 mg of white powder (35 % of theory),
C25H12N604 (407.50)
Melting point: 139-140°C
h) 1-Methyl-2-f(4-amidinopheryl)oxymethyll-imidazo 4 5 b1
pvridin-5-yl-carboxylic acid--N- (2-pyridyl) -N- (2-
ethoxycarbonyl-ethyl)-amide
Prepared by reacting 140 mg 1;0.3 mMol) of 1-methyl-
2-[(4-cyanophenyl)oxymethyl]-imidazo[4,5-b]pyridin-5-yl-
carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-
amide with ethanol saturated by hydrogen chloride and with
ammonium carbonate/ethanol analogously to Example 1g. The
resulting product was purified by chromatography over
silica gel with dichloromethane/ethanol (19:1 to 4:1).
Yield: 48 mg of white powder (36 % of theory),
C26H27N704 (501.57)
Mass spectrum: (M+H)+ = 502
CA 02277949 1999-07-14
- 53 -
Example 9
2-[N-(4-amidinophenyl)-aminomethyl]-benzothiazole-5-
carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide
a) Ethvl 4-fluoro-3-methoxyacetamido-benzoate
A solution of 2.8 g (15.3 mMol) of ethyl 3-amino-4-fluoro-
benzoate (cf. L.S. Fosdick, A.F. Dodds in J. Amer. Chem.
Soc. 65, 2305 (1943)) and 1.56 ml (1.85 g = 17.0 mMol) of
methoxyacetylchloride in 50 m:1 chlorobenzene was stirred
for 1 hour at 50°C and then refluxed for 15 minutes. Then
the solvent was distilled off in vacuo and the crude
product obtained was purified by flash chromatography
(silica gel; dichloromethane/e~thanol = 100:1). The desired
compound, initially oily, solidified within a few days.
Yield: 3.8 g (98 % of theory),,
Rf value: 0.38 (silica gel; dichloromethane/ethanol = 19:1)
b) Ethyl-2-methox~rmethvl-benzothiazole-5-carboxylate
A mixture of 3.0 g (11.7 mMol) of 4-fluoro-3-
methoxyacetamido-benzoic acid and 2.1 g (5.2 mMol) of
Lawesson's reagent was refluxe:d for 6 hours in 90 ml
toluene, mixed with 1.0 g Laweason's reagent and heated to
120°C for another 6 hours. After the solvent was replaced
with xylene the mixture was heated to 180°C for a further 8
hours in a pressurised vessel. Then the solvent was
distilled off in vacuo, the crude product obtained was
purified by flash chromatography (silica gel; ethyl
acetate/petroleum ether = 5:95) and evaporated down again.
Yield: 2.1 g of yellow crystals (72 % of theory),
Rf value: 0.55 (silica gel; ethyl acetate/petroleum ether =
3:7)
c) 2-Methoxymethyl-benzothiazo:le-5-carboxylic acid
A mixture of 2.1 g (8.36 mMol) of ethyl 2-methoxymethyl-
benzothiazole-5-carboxylate and 16 ml of 2N sodium
hydroxide solution was stirred into 60 ml ethanol for 1
CA 02277949 1999-07-14 .''- ~-.'~
- 54 -
hour at room temperature. Then the alcohol was distilled
off, the crude product was taken up in 20 ml water, washed
with 50 ml diethylether and the aqueous phase was acidified
with concentrated hydrochloric acid whilst being cooled
with ice. The pinkish-beige compound thereby precipitated
was suction filtered, washed with water and dried.
Yield: 1.6 g (86 % of theory),
Rf value: 0.12 (silica gel; dichloromethane/ethanol = 29:1)
d) 2-Methoxymethyl-benzothia2:ole-5-carboxylic acid-N-
phenvl-N-(2-ethoxycarbonylethyl)-amide
.-.. A suspension of 1.6 g (7.2 mr!fol) of 2-methoxymethyl-
benzothiazole-5-carboxylic acid in 60 ml dichloromethane
was mixed with 1.6 ml (22 mMol) of thionyl chloride and
refluxed for 1 hour. The solid dissolved after 20 minutes.
After distillation of the liquid components the crude
product was taken up in dichloromethane twice more and each
time the solvent was distilled off. The crude acid
chloride thus obtained was taken up in 50 ml of
tetrahydrofuran, added dropwise to a mixture of 1.4 g (7.2
mMol) of N-(2-ethoxycarbonylethyl)aniline and 3.0 ml (21
mMol) of triethylamine in 50 vml of tetrahydrofuran and
stirred overnight at room temperature. Then the solvent
was distilled off in vacuo, t:he residue was taken up in 30
ml of dichloromethane, this solution was washed with water
and dried with sodium sulphates. After distillation of the
solvent and flash chromatography (silica gel; gradient:
dichloromethane/ethanol 98.5::L.5 to 80:20) the desired
compound was isolated as a brownish oil.
Yield: 2.05 (72 % of theory),
Rf value: 0.40 (silica gel; ethyl acetate/petroleum ether =
1:1)
e) 2- fN- (4-Cyanophe~l) -aminomethyll -benzothiazole-
5-carboxylic acid-N=phenyl-N-(2-ethoxycarbonylethyl)-amide
A mixture of 2.05 g (5.14 mMol.) of 2-methoxymethyl-
benzothiazole-5-carboxylic acid-N-phenyl-N-(2-
CA 02277949 1999-07-14
- 55 -
ethoxycarbonylethyl)-amide and 5.7 ml (5.7 mMol) of a 1M
solution of boron tribromide in dichloromethane was
dissolved in a further 60 ml of dichloromethane and stirred
for 16 hours at room temperat=ure. Then the mixture was
washed with 40 ml of saturated sodium hydrogen carbonate
solution, the organic phase was dried with sodium sulphate
and the solvent was distilled off. The crude
2-bromomethyl-benzothiazole-5-carboxylic acid-N-phenyl-
N-(2-ethoxycarbonylethyl)-amide thus obtained (2.4 g) was
taken up in 5.0 ml of N,N-diisopropyl-ethylamine and mixed
with 0.64 g (5.4 mMol) of 4-amino-benzonitrile. After 1
hour's heating to 130°C the solvent was distilled off in
vacuo and the crude product obtained was purified by flash
chromatography (silica gel; gradient: ethyl
acetate/petroleum ether = 1:3 to 1:1), whilst an orange
foam was obtained when the eluates were evaporated down.
Yield: 1.1 g (44 % of theory),
Rf value: 0.35 (silica gel; ethyl acetate/petroleum ether =
7:3)
f) 2-fN-(4-amidinophe ~1)-aminomethyll-benzothiazole-
5-carboxylic acid-N-phenyl-N-(2-ethoxycarbon~rlethyl)-amide
1.1 g (2.27 mMol) of 2- [N- (4-cyanophenyl) -aminomethyl] -
benzothiazole-5-carboxylic ac_~d-N-phenyl-N-(2-
ethoxycarbonylethyl)-amide wa,~ stirred in 100 ml of ethanol
saturated with hydrogen chloride for 5 hours first at 0°C
and then at room temperature until no more starting
material could be detected by thin layer chromatography.
Then the solvent was distilled off at a maximum bath
temperature of 30°C and the oily residue was taken up in
100 ml of absolute ethanol and mixed with 1.6 g (22 mMol)
of ammonium carbonate. After 18 hours stirring at room
temperature the solvent was distilled off in vacuo and the
crude product was purified by flash chromatography (silica
gel; gradient: water/methanol = 19:1 to 4:1). When the
eluates are evaporated down th.e desired compound is
obtained as a white foam.
CA 02277949 1999-07-14
- 56 -
Yield : 0 . 77 g ( 63 % of theory) ,
Rf value: 0.19 (silica gel; dichloromethane/ethanol = 3:7)
C27H27N503S (501.60)
Mass spectrum: (M+H)+ = 502
Example 10
2-[N-(4-amidinophenyl)-aminomethyl]-benzothiazole-
5-carboxylic acid-N-phenyl-N-~(2-carboxyethyl)-amide
0.45 g (0.84 mMol) of 2-[N-(9:-amidinophenyl)-aminomethyl]-
''~' benzothiazole-5-carboxylic acid-N-phenyl-N-(2-
ethoxycarbonylethyl)-amide were dissolved in 15 ml of
ethanol, mixed with 2 ml of 2N sodium hydroxide solution
and stirred for 4 hours at room temperature. Then the
mixture was acidified with 3 ml of 2N hydrochloric acid and
the solvent was distilled off. The crude product obtained
was taken up in 5 ml dichloromethane/ethanol (2:1) and
filtered to remove the insoluble sodium chloride. After
the distillation of the solvent the desired compound was
obtained as a yellow foam.
Yield: 0.26 g (67 % of theory),
Rf value: 0.47 (silica gel; meahanol/5 % aqueous sodium
chloride = 6:4)
,......
C25H23N5~3S (473.55)
Mass spectrum: (M+H)+ = 474
Example 11
2- [N- (4-amidinophenyl) -aminomethyl]benzothiazol-5-yl-
carboxylic acid-N-(2-pyridyl)--N-(2-methoxycarbonylethyl)-
amide-dihydrochloride
Prepared analogously to Example 9 from 2-[N-(4-
cyanophenyl)-aminomethyl]benzc>thiazol-5-yl-carboxylic acid-
N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide, methanolic
hydrochloric acid, methanol anal ammonium carbonate.
CA 02277949 1999-07-14
_ 57 _
Yield: 68 % of theory,
C25H24N6~3S (488.57)
Rf value: 0.13 (silica gel; methylene chloride/ethanol -
4:1 +a few drops of acetic acid)
EKA mass spectrum . (M+H)+ = 489
Example 12
2-[2-(4-amidinophenyl)ethyl]-benzothiazol-5-yl-carboxylic
acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide-
dihydrochloride
Prepared analogously to Example 9 from 2-(2-(4-
cyanophenyl)ethyl]-benzothiazol-5-yl-carboxylic acid-N-(2-
pyridyl)-N-(ethoxycarbonylmethyl)-amide, ethanolic
hydrochloric acid, ethanol and ammonium carbonate.
Yield: 95 % of theory,
C26H25N5~3S (487.58)
Rf value: 0.20 (silica gel; meahylene chloride/ethanol =
4:1 + a few drops of acetic acid)
EKA mass spectrum: (M+H) + = 4E38
Example 13
2-[N-(4-amidinophenyl)-aminomeahyl]-benzothiazol-5-yl-
carboxylic acid-N-(2-pyridyl)--N-(ethoxycarbonylmethyl)-
amide-dihydrochloride
Prepared analogously to Example 9 from 2-[N-(4-
cyanophenyl)-aminomethyl)-benzothiazol-5-yl-carboxylic
acid-N-(2-pyridyl)-N-(ethoxyca.rbonylmethyl)-amide,
ethanolic hydrochloric acid, ethanol and ammonium
carbonate.
Yield: 68 % of theory,
C25H24N6~3S (488.57)
Rf value: 0.14 (silica gel; met:hylene chloride/ethanol =
CA 02277949 1999-07-14
- 58 -
4:1 + a few drops of acetic acid)
EKA mass spectrum: (M+H)+ = 489
Example 14
2-(N-(4-amidinophenyl)-aminomethyl]-benzothiazol-5-yl-
carboxylic acid-N-(2-pyridyl)-N-(hydroxycarbonylmethyl)-
amide-dihydrochloride
Prepared analogously to ExamF~le 10 from 2-[N-(4-
amidinophenyl)-aminomethyl]-benzothiazol-5-yl-carboxylic
"" acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide-
dihydrochloride and sodium hydroxide solution.
Yield: 90 % of theory,
C23H20N603S (460.52)
Rf value
EKA mass spectrum: (M+H)+ - 461
(M+Na)+ - 483
(M+2Na)++ = 253
Example 15
2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzothiazol-
''" 5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-
amide-hydrochloride
a) 2-fN-(4-Cyanophenyl)-N-methyl-aminomethyll-benzothiazol-
5-yl-carboxylic acid-N-phenyl--N-(2-ethoxycarbonylethyl)-
amide
Prepared analogously to Examp7_e 9e from 4-cyano-N-methyl-
aniline and 2-methoxymethyl-be:nzothiazole-5-carboxylic
acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide.
Yield: 57 % of theory,
Rf value: 0.46 (silica gel; dichloromethane/ethanol =
19:1) .
CA 02277949 1999-07-14
' - .'59 -
b) 2-fN-(4-amidinophenyl)-N-methyl-aminomethvl
benzothiazol-5-yl-carboxylic acid-N-phenyl-N-(2-
ethoxvcarbonylethvl)-amide-h~rdrochloride
Prepared analogously to Example 9 from 2-[N-(4-
cyanophenyl)-N-methyl-aminomethyl]-benzothiazol-5-yl-
carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide,
ethanolic hydrochloric acid, ethanol and ammonium
carbonate.
Yield: 73 % of theory,
C28H29N503S (515.64)
Rf value:0.29 (silica gel; met:hylene chloride/ethanol = 4:1
+ a few drops of acetic acid)
EKA mass spectrum: (M+H) + = 5:L6
Example 16
2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzothiazol-
5-yl-carboxyli:c acid-N-phenyl-~N-(2-hydroxycarbonylethyl)-
amide-hydrochloride
Prepared analogously to Example 10 from 2-[N-(4-
amidinophenyl)-N-methyl-aminomethyl]-benzothiazol-5-yl-
carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-
hydrochloride and sodium hydroxide solution.
Yield: 96 % of theory,
C26H25N5~3S (487.58)
Rf value: 0.48 (Merck RP-8, mei_hanol/5% NaCl solution =
6:4)
EKA mass spectrum: (M+H)+ - 488
(M+2Na)++ = 266.5
CA 02277949 2005-06-O1
27400-188(S)
- 60 -
Example 17
2-[(4-amidinophenyl)thiomethyl]-benzothiazol-5-yl-.
carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-
hydrochloride
Prepared analogously to Example 9 from 2-[(4-
cyanophenyl)thiomethyl]-benzothiazol-5-yl-carboxylic acid-
N-phenyl-N-(2-ethoxycarbonylethyl)-amide, ethanolic
hyd:~-ochloric acid, ethanol and ammonium carbonate.
Yield: 61 % of ,'theory,
C27~~26N403S2 (518.66)
Rf value: 0_27 (silica gel; methylene chloride/ethanol =
4:1 + a few drops of acetic acid)
EKA mass spectrum: (M+H)+ = 519
Example 18
2-[(4-amidinophenyl)thiomethyl]-benzothiazol-5-yl-
car)r~oxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide-
hydrochloride
Prepared analogously to Example 10 from 2-[(4-
amidinophenyl)thio-48- [sic] methyl]-benzothiazol-5-yl-
carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-
hydrochloride and sodium hydroxide solution.
Yield: 95 % of theory,
C25H22N4~3S2 (490.61)
TM
Rf value: 0.25 (Merck RP-8, methanol/5% NaCl solution =
6:4)
EKA mass spectrum: (M+H)+ - 491
(M+Na)+ = 513
CA 02277949 1999-07-14
' - 61 -
Examt~le 19
2-[N-(4-amidinophenyl)-aminomethyl]-benzothiazol-5-yl-
carboxylic acid-N-phenyl-N-(ethoxycarbonylmethyl)-amide-
hydrochloride
Prepared analogously to ExamF~le 9 from 2- [N- (4-
cyanophenyl)-aminomethyl]-ben.zothiazol-5-yl-carboxylic
acid-N-phenyl-N-(ethoxycarbon.ylmethyl)-amide, ethanolic
hydrochloric acid, ethanol and ammonium carbonate.
Yield: 82 0 of theory,
C26H25N5~3S (487.58)
Rf value: 0.21 (silica gel; methylene chloride/ethanol =
4:1 + a few drops of acetic acid)
EKA mass spectrum: (M+H)+ = 488
Example 20
2-[N-(4-amidinophenyl)-aminomethyl]-benzothiazol-5-yl-
carboxylic acid-N-phenyl-N-(hydroxycarbonylmethyl)-amide-
hydrochloride
Prepared analogously to Example 10 from 2-[N-(4-
amidinophenyl)-aminomethyl]-be;nzothiazol-5-yl-carboxylic
acid-N-phenyl-N-(ethoxycarbonylmethyl)-amide-hydrochloride
and sodium hydroxide solution.
Yield: 75 % of theory,
C24H21N5~3S (459.53)
Rf value: 0.14 (silica gel; methylene chloride/ethanol =
4:1 + a few drops of acetic acid)
EKA mass spectrum: (M+H)+ - 460
(M+Na)+ = 482
CA 02277949 1999-07-14
' ~ - 62 -
Example 21
2-[2-(4-amidinophenyl)ethyl]--benzothiazol-5-yl-carboxylic
acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride
Prepared analogously to Example 9 from 2-[2-(4-
cyanophenyl)ethyl]-benzothiaz;ol-5-yl-carboxylic acid-N-
phenyl-N-(2-ethoxycarbonylethyl)-amide, ethanolic
hydrochloric acid, ethanol anal ammonium carbonate.
Yield: 80 % of theory,
C28H28N403S (500.62)
Rf value: 0.30 (silica gel; methylene chloride/ethanol =
4:1 + a few drops of acetic acid)
EKA mass spectrum: (M+H)+ = 501
Example 22
2- [2- (4-amidinophenyl) ethyl] -lbenzothiazol-5-yl-carboxylic
acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide-
hydrochloride
Prepared analogously to Example 10 from 2-[2-(4-
amidinophenyl)ethyl]-benzothiazol-5-yl-carboxylic acid-N-
phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and
,,....
sodium hydroxide solution.
Yield: 77 % of theory,
C26H24N4~3S (472.57)
Rf value: 0.18 (silica gel; methylene chloride/ethanol =
4:1 + a few drops of acetic acid)
EKA mass spectrum: (M+H)+ - 473
(M+Na)+ - 495
(M+H+Na)++ = 259
CA 02277949 1999-07-14
- 63 -
Example 23
2-[N-(4-amidinophenyl)-aminomethyl]-benzothiazol-5-yl-
carboxylic acid-N-(n-propyl)-N-(2-ethoxycarbonylethyl)-
amide-hydrochloride
Prepared analogously to Example 9 from 2-(N-(4-
cyanophenyl)-aminomethyl]-benzothiazol-5-yl-carboxylic
acid-N-(n-propyl)-N-(2-ethoxycarbonylethyl)-amide,
ethanolic hydrochloric acid, ethanol and ammonium
carbonate.
,,.,., Yield: 83 % of theory,
C24H29N5~3 (467.59)
Rf value: 0.31 (silica gel; meahylene chloride/ethanol -
4:1 + a few drops of acetic acid)
EKA mass spectrum: (M+H)+ - 468
(2M+H)+ = 935
Example 24
2-[N-(4-amidinophenyl)-aminomeahyl]-benzothiazol-5-yl-
carboxylic acid-N-(n-propyl)-td-(2-hydroxycarbonylethyl)-
amide-hydrochloride
Prepared analogously to Example 10 from 2-[N-(4-
amidinophenyl)-aminomethyl]-be:nzothiazol-5-yl-carboxylic
acid-N-(n-propyl)-N-(2-ethoxycarbonylethyl)-amide-
hydrochloride and sodium hydroxide solution.
Yield: 75 % of theory,
C22H25N5~3S (439.54)
Rf value: 0.14 (silica gel; methylene chloride/ethanol =
4:1 + a few drops of acetic acid)
EKA mass spectrum: (M+H)+ - 440
(M+H+Na)++ = 231.6
CA 02277949 1999-07-14
- 64 -
Example 25
1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-
5-yl-carboxylic acid-N-pheny].-N-(2-ethoxycarbonylethyl)-
amide-hydrochloride
a) 4-Methylamino-3-nitro-benzoic acid-N-phenyl-N-(2-ethoxv-
carbonylethyl ) -amide
To a solution of 24.7 g (0.115 mol) of 4-methylamino-3-
nitro-benzoic acid chloride and 22.3 g (0.115 mol) of
,"~," N-(2-ethoxy-carbonylethyl)-aniline in 300 ml of
tetrahydrofuran, 13.1 g (0.13 mol) of triethylamine were
added dropwise in 15 minutes, with stirring, at room
temperature. After 2 hours stirring the solvent was
distilled off in a water-jet vacuum and the residue was
mixed with 700 ml of water with stirring. The mixture was
extracted 3 times with 200 ml of dichloromethane, the or-
ganic extract was washed twice with 200 ml of 2N
hydrochloric acid and twice with 300 ml of water and dried
over sodium sulphate. The solvent was then distilled off
and the oily product thus obt<~ined was purified by column
chromatography (1 kg silica gE~l; eluant: petroleum
ether/ethyl acetate = 2:1).
Yield: 35.0 g (82 % of theory),
Rf value: 0.28 (silica gel; dichloromethane/ethanol = 50:1)
b) 3-Amino-4-methylamino-benzoic acid-N-phenyl-N-(2-ethoxv-
carbonyleth~rl ) -amide
12.1 g (0.0326 mol) of 4-methylamino-3-nitro-benzoic acid-
N-phenyl-N-(2-ethoxycarbonylet:hyl)-amide were hydrogenated
in 300 ml ethanol and 150 ml cLichloromethane after the
addition of about 4 g of palla~dium/charcoal (10%) at room
temperature and under a hydrogen pressure of 5 bar. Then
the catalyst was filtered off and the filtrate was
evaporated down. The crude product thus obtained was
reacted without further purification.
CA 02277949 1999-07-14
- 65 -
Yield: 10.6 g (95 % of theor~~) ,
Rf value: 0.19 (silica gel; dichloromethane/ethanol = 50:1)
c) 1-Methyl-2-fN-(4-cyanophenyl)-aminomethyll-benzimidazol-
5-vl-carboxylic acid-N-phenyl-N-(2-ethoxvcarbonvlethyl)-
amide
6.17 g (0.035 mol) of N-(4-cyanophenyl)glycine and 5.68 g
(0.035 mol) of N,N'-carbonyld.iimidazole were refluxed in
300 ml of tetrahydrofuran for 30 minutes, then 10.6 g
(0.032 mol) of 3-amino-4-methylamino-benzoic acid-N-phenyl-
N-(2-ethoxycarbonylethyl)-amide were added and the mixture
..- was refluxed for a further five hours. Then the solvent
was distilled off in vacuo, the residue was dissolved in
150 ml of glacial acetic acid and refluxed for one hour.
Then the glacial acetic acid was distilled off in vacuo,
the residue was dissolved in .about 300 ml of
dichloromethane, the solution was washed twice with about
150 ml water and then dried over sodium sulphate. After
evaporation of the solvent the, crude product thus obtained
was purified by column chromai:ography (800 g silica gel;
eluant: dichloromethane with .l-2 o ethanol).
Yield: 8.5 g (57 0 of theory),.
Rf value: 0.51 (silica gel; dichloromethane/ethanol = 19:1)
d) 1-Methyl-2- N- (4-amidinot~hEnvl) -aminomethvl
benzimidazol-5-yl-carboxylic skid-N phenyl-N-(2-
ethoxycarbonylet ~1 ) -amide-hydrochloride
1.2 g (2.49 mMol) of 1-methyl-2- [N- (4-cyanophenyl) -
aminomethyl]-benzimidazol-5-yl.-carboxylic acid-N-phenyl-N-
(2-ethoxycarbonylethyl)-amide were stirred in 100 ml of
saturated ethanolic hydrochloric acid for 6 hours at room
temperature. Then the mixture was evaporated to dryness in
vacuo, the residue was dissolved in 100 ml of ethanol,
mixed with 2.5 g (26 mMol) of ammonium carbonate and
stirred overnight at room temperature. After distillation
of the solvent the crude product thus obtained was purified
by column chromatography (100 g silica gel; eluant:
CA 02277949 1999-07-14
' - 66 -
dichloromethane/ethanol = 4:1). By concentrating the
eluates the desired compound was obtained as a white,
amorphous solid.
Yield: 1 .10 g (83 % of theory) ,
Rf value: 0.18 (silica gel; dichloromethane/ethanol = 4:1)
C28H3pN603 x HC1 (498.6)
EKA mass spectrum: (M+H)+ - 499
(M+2H)++ - 250
( M+H+Na ) -~+ = 2 61
Example 26
1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-
5-yl-carboxylic acid-N-phenyl.-N-(2-hydroxycarbonylethyl)-
amide
A mixture of 300 mg (0.56 mMol) of 1-methyl-2-[N-(4-
amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic
acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-
hydrochloride, 15 ml of ethanol, 4 ml of water and 120 mg
(3.0 mMol) of sodium hydroxide was stirred for two hours at
room temperature. Then the mixture was diluted with about
20 ml of water and made weakly alkaline with glacial acetic
-- acid. The product which crystallised out was suction
filtered, washed with water a:nd dried at 60°C in vacuo.
Yield: 250 mg (95 % of theory),
C26H26N6~3 (470.5)
EKA mass spectrum: (M+H)+ - 471
( M+H+Na ) +~~ = 2 4 7
(M+2Na)++ - 258
CA 02277949 1999-07-14
- 67 -
Example 27
1-Methyl-2-[(4-amidinophenyl)thiomethyl]-benzimidazol-5-yl-
carboxylic acid-N-(n-propyl)-~N-(2-ethoxycarbonylethyl)-
amide-hydrochloride
a) 4-Methylamino-3-chloracetamido-benzoic acid-N-(n-
propvl)-N-(2-ethoxycarbonylet.hyl)-amide
A solution of 1.8 g (5.9 mMol) of 3-amino-4-methylamino-
- 10 benzoic acid-N-(n-propyl)-N-(2-ethoxycarbonylethyl)-amide
[prepared analogously to 3-amino-4-ethylamino-benzoic acid-
..... N-phenyl-N-(2-ethoxycarbonylethyl)-amide], 1.1g (6.8 mMol)
of N,N'-carbonyldiimidazole and 0.65 g (6.9 mMol) of
chloroacetic acid in 75 ml tetrahydrofuran was stirred for
1 hour at room temperature. Then the solvent was distilled
off in vacuo, and the crude product was purified by flash
chromatography (silica gel; m~ethylene chloride/ethanol =
49:1) .
Yield: 1.7 g (77% of theory) yellow oil,
Rf value: 0.58 (silica gel; ethyl acetate/ethanol/ammonia
- 90:10:1)
b) 2-Chloromethyl-1-methyl-benzimidazol-5-yl-carboxylic
acid-N- !n-propyl) -N- (2-ethoxyc.arbonylethyl) -amide
,.-.
1.6 g (4.3 mMol) of 4-methylamino-3-chloracetamido-benzoic
acid-N-(n-propyl)-N-(2-ethoxyc:arbonylethyl)-amide were
heated to 100°C in 25 ml of acetic acid for 30 minutes.
Then the solvent was distilled off, the crude product was
taken up in 40 ml methylene chloride/ethanol (9:1) and
washed with 20 ml saturated sodium hydrogen carbonate
solution. The organic phase was dried with sodium sulphate
and evaporated down.
Yield: 1.5 g (100% of theory) of brown oil,
Rf value: 0.63 (silica gel; ethyl acetate/ethanol/ammonia
- 90:10:1)
CA 02277949 1999-07--14
- 68 -
c) 1-Methyl-2- f (4-c~rano~heny'L~ thiomethyll -benzimidazol-5-
yl-carboxylic acid-N- (n-prop~,~l) -N- (2-ethoxycarbonylethyl)
amide
A mixture of 1.5 g (4.1 mMol) of 2-chloromethyl-1-methyl-
benzimidazol-5-yl-carboxylic acid-N-(n-propyl)-N-
(2-ethoxycarbonylethyl)-amide and 0.65 g (4.8 mMol) of p-
cyanothiophenol was heated in 10 ml of dimethylformamide
and 10 ml of diisopropylethyl.amine for 1 hour to 100°C.
The solvent was distilled off in vacuo, the crude product
was dissolved in 30 ml ethyl acetate, washed with 30 ml
water, and after concentration purified by flash
chromatography (silica gel; m.ethylene chloride/ethanol
(49:1 to 19:1) .
Yield: 1.5 g (79% of theory) of brown oil,
Rf value: 0.65 (silica gel; et:.hyl acetate/ethanol/ammonia
- 90:10:1)
d) 1-Methyl-2-f(4-amidinophenyrl)thiomethyll-benzimidazol-5-
-carboxylic acid-N- (n =propel) -N- (2-ethoxycarbonylethyl) -
amide-hydrochloride
1.4 g (3. 01 mMol) of 1-methyl-2- [ (4-cyanophenyl) -
thiomethyl]-benzimidazol-5-yl~-carboxylic acid-N-(n-propyl)-
N-(2-ethoxycarbonylethyl)-amide were stirred in 50 ml of
ethanol saturated with hydrogesn chloride for 5 hours first
at 0°C, later at room temperature, until no more starting
material could be detected by thin layer chromatography.
Then the solvent was distilled off at a maximum bath
temperature of 30°C, the oily residue was taken up in 40 ml
of absolute ethanol and mixed with 2.8 g of ammonium
carbonate. After 18 hours the solvent was distilled off in
vacuo and the crude product ways purified by flash
chromatography (silica gel; meahylene chloride/ethanol =
19:1 to 4:1).
Yield: 1.3 g (83% of theory) as a light beige solid,
Rf value: 0.29 (silica gel; ethyl acetate/ethanol/ammonia
- 50:45:5)
CA 02277949 1999-07-14
- 69 -
C25H31N603S (481.62)
EKA mass spectrum: (M+H)+ = 482
Example 28
1-Methyl-2-[(4-amidinophenyl)thiomethyl]-benzimidazol-5-yl-
carboxylic acid-N-(n-propyl)-N-(2-hydroxycarbonylethyl)-
amide-hydrochloride
0.52 g (1.0 mMol) of 1-Methyl-2-[(4-amidinophenyl)-
thiomethyl]-benzimidazol-5-yl-carboxylic acid-N-(n-propyl)-
""r' N-(2-ethoxycarbonylethyl)-amide-hydrochloride was dissolved
in 15 ml ethanol, mixed with 5 ml of 2N sodium hydroxide
solution and stirred for 2 hours at room temperature. Then
5 ml of water were added, the alcohol was distilled off,
and it was acidified with concentrated hydrochloric acid.
The water was distilled off in vacuo, and the crude product
was taken up in 5 ml of ethanol and filtered to remove the
insoluble sodium chloride. After the solvent had been
distilled off the title compound was obtained as a white
solid.
Yield: 0.43 g (88% of theory),
Rf value: 0.19 (silica gel; ethyl acetate/ethanol/ammonia
- 50:45:5)
C23H27N503S (453.57)
EKA mass spectrum: (M+H)+ - 454
( M+Na ) + = 4 7 6
Example 29
1-Methyl-2-[(4-amidinophenyl)thiomethyl]-benzimidazol-5-yl-
carboxylic acid-N-(2-methylpro:pyl)-N-(2-
ethoxycarbonylethyl)-amide-hydrochloride
Prepared analogously to Example 27 from 1-methyl-2-[(4-
cyanophenyl)thiomethyl]-benzim:idazol-5-yl-carboxylic acid-
(N-(2-methylpropyl-N-(2-ethoxycarbonylethyl)-amide,
CA 02277949 1999-07-14
- 70 -
ethanolic hydrochloric acid, ethanol and ammonium
carbonate.
Yield: 83 % of theory,
C25H31N603S (495.65)
Rt value: 0.30 (silica gel; ethyl acetate/ethanol/ammonia
- 50:45:5) .
EKA mass spectrum: (M+H) + = 496
Example 30
1-Methyl-2-[(4-amidinophenyl)thiomethyl]-benzimidazol-5-yl-
carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-
hydrochloride
Prepared analogously to ExamF>le 27 from 1-methyl-2-[(4-
cyanophenyl)thiomethyl]-benzi.midazol-5-yl-carboxylic acid-
N-phenyl-N-(2-ethoxycarbonyleahyl)-amide, and ethanolic
hydrochloric acid, ethanol anal ammonium carbonate.
Yield: 90 % of theory,
C28H29N503S (515.64)
Rf value:0.24 (silica gel; ethyl acetate/ethanol/ammonia =
50:45:5)
EI~A mass spectrum: (M+H) + - 516
(M+H+Na)++ = 269.7
Example 31
1-Methyl-2-[(4-amidinophenyl)thiomethyl]-benzimidazol-5-yl-
carboxylic acid-N-phenyl-N-(2~-hydroxycarbonylethyl)-amide-
hydrochloride
Prepared analogously to Example 28 from 1-methyl-2-[(4-
amidinophenyl)thiomethyl-benzimidazol-5-yl-carboxylic acid-
N-phenyl-N-(2-ethoxycarbonylet:hyl)-amide-hydrochloride and
sodium hydroxide solution.
Yield: 76 % of theory,
CA 02277949 1999-07-14
- 71 _
C26H25N5~3S (487.58)
Rf value: 0.31 (silica gel; ethyl acetate/ethanol/ammonia
- 50:45:5)
EKA mass spectrum: (M+H)+ - 488
( M+Na ) + _ 510
Example 32
1-Methyl-2-[(4-amidinophenyl)oxymethyl]-benzimidazol-5-yl
sulphonic acid-N-(1-methyl-piperidin-4-yl)-N-methyl-amide
hydrochloride
,,....
a) 4-Chloro-3-nitrobenzenesulphonic acid-N-(1-methyl-
piperidin-4-yl)-N-methyl-amide
To a solution of 2.2 ml (15 mbiol) of 1-methyl-4-
methylamino-piperidine in 60 ml pyridine, 3.8 g (15 mMol)
of 4-chloro-3-vitro-benzenesul.phonic acid chloride were
added, in batches, whilst cooling with ice. The mixture was
then stirred for two hours with cooling, then evaporated to
dryness, the residue was mixef. with about 50 ml of water
and made alkaline with concentrated ammonia whilst stirring
vigorously. The crude product precipitated was suction
filtered and purified by column chromatography (250 g
..-- silica gel, eluant: dichloromethane with 1.5% ethanol).
Yield: 1.6 g (31% of theory),
C13H18C1N304S (347.8)
Rf value: 0.19 (silica gel; dichloromethane/ethanol = 19:1)
b) 4-Methylamino-3-nitrobenzenesulphonic acid-N-methyl-N-
(1-methylpiperidin-4-yl)-amide
1.6 g (4.6 mMol) of 4-chloro-3-nitrobenzenesulphonic acid-
N-methyl-N-(1-methyl-piperidin-4-yl)-amide was mixed with
30 ml of 40% methylamine solution and stirred in a sealed
flask for four hours at room temperature. Then the mixture
was diluted with about 40 ml of water, the product
precipitated was suction filtered, washed with water and
dried.
CA 02277949 1999-07-14
- 72 -
Yield: 1.5 g (95% of theory),
C14H22N4~4S (343.4)
Rf value: 0.45 (silica gel; dichloromethane/ethanol - 4:1)
c) 3-Amino-4-methylaminobenze:nesulphonic acid-N-methyl-N-
(1-methylpi~eridin-4-yl) -amide
1.5 g (4.4 mMol) of 4-methylamino-3-nitrobenzenesulphonic
acid-N-methyl-N-(1-methyl-piperidin-4-yl)-amide were
dissolved in 100 ml methanol and catalytically hydrogenated
at room temperature and under 5 bar hydrogen pressure (10%
palladium on charcoal). Then the catalyst was filtered off
'"' and the filtrate was evaporated down. The resulting oily
product was further reacted without any purification.
Yield: 1.4 g (100% of theory),
C14H24N4~2S (312.4)
Rf value: 0.33 (silica gel; dichloromethane/ethanol = 4:1)
d) 1-Methyl-2-f(4-cyanophenyl)oxymethyll-benzimidazol-5-vl-
sulfonic acid-N-methyl-N-(1-m~~thvl-piperidin-4-vl)-amide
532 mg (3.0 mMol) of 4-cyanop:henyloxyacetic acid and 486 mg
(3.0 mMol) of 1,1'-carbonyldi:imidazole were dissolved in
40 ml of tetrahydrofuran and _refluxed for 15 minutes. Then
700 mg (2.24 mMol) of 3-amino-4-methylaminobenzenesulphonic
,"" acid-N-methyl-N-(1-methyl-piperidin-4-yl)-amide were added
and boiling was continued for a further eight hours. Then
the mixture was evaporated down and the resulting oily
residue was refluxed in 30 ml of glacial acetic acid for
one hour. The glacial acetic acid was distilled off, the
residue was mixed with about 30 ml of water and made
alkaline with concentrated amrnonia, and the solution was
extracted three times with about 20 ml of dichloromethane.
The organic phases were dried and evaporated down. The
resulting product was further reacted without any
purification.
Yield: 400 mg (39% of theory).
C23H27N5~3S (453.6)
Rf value: 0.37 (silica gel; dichloromethane/ethanol - 4:1)
CA 02277949 1999-07-14
- '73 -
e) 1-Methyl-2-((4-amidinophenyl)oxymethyll-benzimidazol-5-
yl-sulphonic acid-N-methyl-N-~1-methyl~iperidin-4-yl)-
amide-hydrochloride
Prepared analogously to Example 25d from 400 mg of 1-
methyl-2-[(4-cyanophenyl)oxymethyl]-benzimidazol-5-yl-
sulphonic acid-N-methyl-N-(1-vmethylpiperidin-4-yl)-amide
with ethanolic hydrochloric acid and ammonium carbonate.
Yield: 370 mg (83's of theory) .
C23H30N6~3S (470.6)
EKA mass spectrum: (M+H)+ - 471
,~-~
(M+2H) ++ = 236
Example 33
1-Methyl-2-[(4-amidinophenyl)oxymethyl]-benzimidazol-5-yl-
sulphonic acid-N-methyl-N-phenyl-amide-hydrochloride
Prepared analogously to Examp'.Le 32 from 1-methyl-2-((4-
cyanophenyl)-oxymethyl]-benzinnidazol-5-yl-sulphonic acid-N-
methyl-N-phenyl-amide and ethanolic hydrochloric acid,
ethanol and ammonium carbonate:.
Yield: 46 0 of theory,
C23H23N5~3S (449.5)
EKA mass spectrum: (M+H)+ - 450
(M+H+Methanol)+ = 482
(M+2H)++ - 223
Example 34
1-Methyl-2-[(4-amidinophenyl)oxymethyl]-benzimidazol-5-yl-
sulphonic acid-N-(3-ethoxycarbonyl-n-propyl)-N-phenyl-
amide-hydrochloride
Prepared analogously to Example 32 from 1-methyl-2-[(4-
cyanophenyl)oxymethyl]-benzimidazol-5-yl-sulphonic acid-N-
CA 02277949 1999-07-14
- 74 -
(3-ethoxycarbonyl-n-propyl)-rf-phenyl-amide, ethanolic
hydrochloric acid, ethanol and ammonium carbonate.
Yield: 57 % of theory,
C28H31N5~5S (549.7)
EKA mass spectrum: (M+H)+ = 550
Example 35
1-Methyl-2-[(3-amidinophenyl)oxymethyl]-benzimidazol-5-yl-
sulphonic acid-pyrrolidide-hydrochloride
Prepared analogously to Example 32 from 1-methyl-2-[(3-
cyanophenyl)oxymethyl]-benzimidazol-5-yl-sulphonic acid-
pyrrolidide, ethanolic hydrochloric acid, ethanol and
ammonium carbonate.
Yield: 71 % of theory,
C20H23N5~3S (413.5)
EKA mass spectrum: (M+H)+ = 4:14
Example 36
1-Methyl-2- [2- (4-amidinopheny:l) ethyl] -benzimidazol-5-yl-
carboxylic acid-N-phenyl-N-(3~-methoxycarbonylpropyl)-amide-
., dihydrochloride
Prepared analogously to Examp:Le 25d from 1-methyl-2- [2- (4-
cyanophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-
phenyl-N-(3-tert.butyloxycarbonylpropyl)-amide and
methanolic hydrochloric acid, methanol and ammonium
carbonate.
Yield: 83.5 % of theory,
Rf value: 0.17 (silica gel; dichloromethane/ethanol = 4:1)
C29H31N5~3 (497.6)
EKA mass spectrum: (M+H)+ - 498
(M+H+Na)++ = 260.7
CA 02277949 1999-07-14
- ;~ 5 _
Example 37
1-Methyl-2- [2- (4-amidinopheny:l) ethyl] -benzimidazol-5-yl-
carboxylic acid-N-phenyl-N-(3-hydroxycarbonylpropyl)-amide-
hydrochloride
Prepared analogously to Examp:Le 26 from 1-methyl-2-((4-
amidinophenyl)aminomethyl]-benzimidazol-5-yl-carboxylic
acid-N-phenyl-N-(3-methoxycarbonylpropyl)-amide-
dihydrochloride and sodium hydroxide solution.
Yield: 92 % of theory,
.- Rf value: 0.09 (silica gel; dichloromethane/ethanol = 4:1)
C28H29N5~3 (483.6)
EKA mass spectrum: (M+H)+ - 484
(M+Na) + - 506
( M+H+Na ) ++ = 2 5 3 . 7
Example 38
1-Methyl-2-[N-(4-amidinophenyl.)-aminomethylJ-benzimidazol-
5-yl-carboxylic acid-N-phenyl-N-(3-ethoxycarbonylpropyl)-
amide-dihydrochloride
-.. a) 1-Methyl-2- fN- (4-cyanoQhenvlL-aminomethyll -benzimidazol-
5-vl-carboxylic acid-N-phenyl-N-(3-tert.butyloxy-
carbonylpropyl)-amide
Prepared analogously to Example 25c from N-(4-cyanophenyl)-
glycine and 3-amino-4-methylam.ino-benzoic acid-N-phenyl-
N-(3-tert.butyloxycarbonylpropyl)-amide.
Yield: 65 % of theory,
Rf value: 0.17 (silica gel; dichloromethane/methanol =
19:1)
b) 1-Methyl-2- (N- (4-amidinophenyl) -aminomethyl~ -
benzimidazol-5-yl-carboxylic acid-N-phenyl-
N-~3-ethoxycarbonyl,propel)-amide-dihydrochloride
CA 02277949 1999-07-14
- 76 -
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-
cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic
acid-N-phenyl-N-(3-tert.buty] _oxycarbonylpropyl)-amide and
ethanolic hydrochloric acid, ethanol and ammonium
carbonate.
Yield: 68 % of theory,
Rf value: 0.12 (silica gel; dichloromethane/ethanol = 4:1)
C29H32N6~3 (512.6)
EKA mass spectrum: (M+H)+ - 513
( M+H+Na ) ++' - 2 6 8
''~ Example 39
1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol
5-yl-carboxylic acid-N-phenyl-N-(3-hydroxycarbonylpropyl)
amide-hydrochloride
Prepared analogously to Example 26 from 1-methyl-2-[N-(4-
amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic
acid-N-phenyl-N-(3-ethoxycarbonylpropyl)-amide-
dihydrochloride and sodium hydroxide solution.
Yield: 73.5 % of theory,
C27H28N6~3 (484.6)
EKA mass spectrum: (M+H)+ - 485
(M+2H) ++ - 243
( M+H+Na ) ++ = 2 5 4
Example 40
1-Methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-
carboxylic acid-N-phenyl-N-(ethoxycarbonylmethyl)-amide-
hydrochloride
Prepared analogously to Example 25d from 1-methyl-2-[2-(4-
cyanophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-
CA 02277949 1999-07-14
- '7 7 -
phenyl-N-(ethoxycarbonylmethyl)-amide and ethanolic
hydrochloric acid, ethanol anal ammonium carbonate.
Yield: 73 % of theory,
Rf value: 0.15 (silica gel; d:ichloromethane/ethanol = 4:1)
C2gH29N5~3 (483.6)
EKA mass spectrum: (M+H)+ - 484
(M+H+Na)++ = 253.7
Example 41
1-Methyl-2-[2-(4-amidinopheny:l)ethyl]-benzimidazol-5-yl-
carboxylic acid-N-phenyl-N-(h;ydroxycarbonylmethyl)-amide-
hydrochloride
Prepared analogously to Example 26 from 1-methyl-2-[2-(4-
amidinophenyl)ethyl]benzimida:~ol-5-yl-carboxylic acid-N-
phenyl-N-(ethoxycarbonylmethy:L)-amide-hydrochloride and
sodium hydroxide solution.
Yield: 97 % of theory,
C26H25N5~3 (455.5)
EKA mass spectrum: (M+H)+ -- 456
(M+Na) + -- 478
(M+2Na) ++ _- 250 . 6
Example 42
1-Methyl-2-[(4-amidinophenyl)oxymethyl]-benzimidazol-5-yl-
carboxylic acid-N-phenyl-N-(et.hoxycarbonylmethyl)-amide-
hydrochloride
Prepared analogously to Example 25d from 1-methyl-2-[(4-
cyanophenyl)oxymethyl]-benzimidazol-5-yl-carboxylic acid-N-
phenyl-N-(ethoxycarbonylmethyl)-amide and ethanolic
hydrochloric acid, ethanol and ammonium carbonate.
Yield: 76 % of theory,
Rf value: 0.17 (silica gel; dichloromethane/ethanol = 4:1)
CA 02277949 1999-07-14
- 78 -
c27H27N5~4 (485.6)
EKA mass spectrum: (M+H)+ - 486
( M+H+Na ) +~~ - 2 5 4 . 7
Example 43
1-Methyl-2-[(4-amidinophenyl)oxymethyl]-benzimidazol-5-yl-
carboxylic acid-N-phenyl-N-(hydroxycarbonylmethyl)-amide-
hydrochloride
Prepared analogously to Example 26 from 1-methyl-2-[(4-
amidinophenyl)oxymethyl]-benzimidazol-5-yl-carboxylic acid-
N-phenyl-N-(ethoxycarbonylmethyl)-amide-hydrochloride and
sodium hydroxide solution.
Yield: 58 % of theory,
C25H23N5~4 (457.5)
EKA mass spectrum: (M+H)+ - 458
(M+Na) + - 480
(M+2Na) ++ = 251 . 6
Example 44
1-Methyl-2-[N-(4-amidinopheny:L)-aminomethyl]-benzimidazol-
5-yl-carboxylic acid-N-phenyl-N-(ethoxycarbonylmethyl)-
amide-hydrochloride
Prepared analogously to Example 25d from 1-methyl-2-[N-
(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic
acid-N-phenyl-N-(ethoxycarbonylmethyl)-amide and ethanolic
hydrochloric acid, ethanol and ammonium carbonate.
Yield: 74 % of theory,
Rf value: 0.12 (silica gel; dichloromethane/ethanol = 4:1)
C27H28N603 (484.6)
EKA mass spectrum: (M+H)+ - 485
3 5 ( M+H+Na ) ++ = 2 5 4
CA 02277949 1999-07-14
- '19 -
Example 45
1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-
5-yl-carboxylic acid-N-phenyl-N-(hydroxycarbonylmethyl)-
amide-hydrochloride
Prepared analogously to Example 26 from 1-methyl-2-[N-(4-
amidinophenyl)-aminomethyl]-b~enzimidazol-5-yl-carboxylic
acid-N-phenyl-N-(ethoxycarbon~ylmethyl)-amide-hydrochloride
and sodium hydroxide solution.
Yield: 84 % of theory,
.- C25H24N6~3 (456.5)
EKA mass spectrum: (M+H)+ .- 457
(M+Na) + .- 479
(M+2Na) ++ :- 251
Example 46
1-Methyl-2-[(4-amidinophenyl)oxymethyl]-benzimidazol-5-yl
carboxylic acid-N-(4-pyrimidy:L)-N-(2-ethoxycarbonylethyl)
amide-hydrochloride
Prepared analogously to Example 25d from 1-methyl-2-
,..- [(4-cyanophenyl)oxymethyl]-benzimidazol-5-yl-carboxylic
acid-N-(4-pyrimidyl)-N-(2-ethoxycarbonylethyl)-amide and
ethanolic hydrochloric acid, eahanol and ammonium
carbonate.
Yield: 14 % of theory,
C26H27N7~4 (501.6)
Mass spectrum: (M+H)+ = 502
CA 02277949 1999-07-14
- 80 -
Example 47
1-Methyl-2-[(4-amidinophenyl)oxymethyl]-benzimidazol-5-yl-
carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-
amide-dihydrochloride
Prepared analogously to Example 25d from 1-methyl-2-
[(4-cyanophenyl)oxymethyl]-benzimidazol-5-yl-carboxylic
acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide and
ethanolic hydrochloric acid, ethanol and ammonium
carbonate.
"~,. Yield : 44 0 of theory,
Rf value: 0.12 (silica gel; dichloromethane/ethanol = 4:1)
C26H26N6~4 (486.5)
EKA mass spectrum: (M+H)+ - 487
(M+2H)++ - 244
( M+H+Na ) ++ = 2 5 5
Exam-ple 48
1-Methyl-2-[(4-amidinophenyl)oxymethyl]-benzimidazol-5-yl-
carboxylic acid-N-(2-pyridyl)--N-(hydroxycarbonylmethyl)-
amide-hydrochloride
Prepared analogously to Example 26 from 1-methyl-2-[(4-
amidinophenyl)oxymethyl]-benzimidazol-5-yl-carboxylic acid-
N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide-
dihydrochloride and sodium hydroxide solution.
Yield: 85 % of theory,
C24H22N604 (458.5)
EKA mass spectrum: (M+H)+ -. 459
(M+Na)+ - 481
(M+2Na)++ = 252
CA 02277949 1999-07-14
- 81 -
Example 49
1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-
5-yl-carboxylic acid-N-(2-pyridyl)-
N-(ethoxycarbonylmethyl)-amide-dihydrochloride
a) 1-Methyl-2- fN- (4-cyanophen~Yl) -aminomethyll -benzimidazol-
5-vl-carboxylic acid-N-(2-pyr:idyl)-N-ethoxycarbonvlmethyl-
amide
Prepared analogously to Examp:Le 25c from N-(4-cyanophenyl)-
glycine and 3-amino-4-methylamino-benzoic acid-
N-(2-pyridyl)-N-ethoxycarbony:Lmethyl-amide.
Yield: 24 % of theory,
Rf value: 0.56 (silica gel; dichloromethane/methanol = 4:1)
b) 1-Methvl-2- fN- (4-amidinophenyl) -aminomethyll -
benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-
N-(ethoxycarbonylmet ~l ) -amide'-dihydrochloride
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-
cyanophenyl)-aminomethyl]-ben2:imidazol-5-yl-carboxylic
acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide and
ethanolic hydrochloric acid, ethanol and ammonium
carbonate.
Yield: 70 % of theory,
Rf value: 0.16 (silica gel; di~~hloromethane/ethanol = 4:1)
C26H27N7~3 (485.6)
EKA mass spectrum: (M+H)+ - 486
(M+2H)++ - 243.7
(M+H-Na)++ = 254.6
_.__~__.__. _________~___.._. ._______..~____._.... ..
CA 02277949 1999-07-14
- 82 -
Example 50
1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl)-benzimidazol-
5-yl-carboxylic acid-N-(2-pyridyl)-
N-(hydroxycarbonylmethyl)-amide-hydrochloride
Prepared analogously to Example 26 from 1-methyl-2-[N-(4-
amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic
acid-N-(2-pyridyl)-N-(ethoxyc:arbonylmethyl)-amide-
dihydrochloride and sodium hydroxide solution.
Yield: 91 0 of,'theory,
C24H23N7~3 (457.5)
EKA mass spectrum: (M+H)+ - 458
(M+Na) + - 480
(M+2Na)++ = 251.7
Example 51
1-Methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-
carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-
amide-dihydrochloride
Prepared analogously to Example 25d from 1-methyl-2-(2-(4
.-- cyanophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2
pyridyl)-N-(ethoxycarbonylmethyl)-amide, ethanolic
hydrochloric acid, ethanol and ammonium carbonate.
Yield: 90 % of theory,
Rf value: 0.17 (silica gel; dichloromethane/ethanol = 4:1)
C27H28N6~3 (484.6)
EKA mass spectrum: (M+H)+ - 485
(M+2H)++ - 243
(M+H+Na)++ = 254
CA 02277949 1999-07-14
- 83 -
Example 52
1-Methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl
carboxylic acid-N-(2-pyridyl)-N-(hydroxycarbonylmethyl)
amide-hydrochloride
Prepared analogously to Example 26 from 1-methyl-2-[2-(4-
amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-
(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide-dihydrochloride
and sodium hydroxide solution.
Yield: 89 % of theory,
C25H24N6~3 (456.5)
EKA mass spectrum: (M+H)+ .- 457
(M+Na) + -- 479
Example 53
1-Methyl-2-[N-(4-amidinopheny:L)-aminomethyl]-benzimidazol-
5-yl-carboxylic acid-N-phenyl--N-(2-methoxyarbonylethyl)-
amide-hydrochloride
Prepared analogously to Example 25d from 1-methyl-2-[N-
(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic
acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide and
methanolic hydrochloric acid, methanol and ammonium
carbonate.
Yield: 87 % of theory,
Rf value: 0.11 (silica gel; dichloromethane/ethanol = 4:1)
C27H28N6~3 (484.6)
EKA mass spectrum: (M+H) + - 485
(M+2H)++ - 243
( M+H+Na ) ++ = 2 5 4
CA 02277949 1999-07-14
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Example 54
1-Methyl-2-[(4-amidinophenyl)oxymethyl)-benzimidazol-5-yl-
carboxylic acid-N-phenyl-N-(2,-ethoxycarbonylethyl)-amide-
hydrochloride
Prepared analogously to Example 25d from 1-methyl-2-
[(4-cyanophenyl)oxymethyl)-benzimidazol-5-yl-carboxylic
acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide and ethanolic
hydrochloric acid, ethanol and ammonium carbonate.
Yield: 79.5 % of theory,
~~ C28H29N5~4 (499.6)
Rf value: 0.15 (silica gel; dichloromethane/ethanol = 4:1)
EKA mass spectrum: (M+H)+ - 500.0
( M+H+Na ) ++ - 2 61. 7
Example 55
1-Methyl-2-[(4-amidinophenyl)oxymethyl)-benzimidazol-5-yl
carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide
hydrochloride
Prepared analogously to Examp:Le 26 from 1-methyl-2-[(4-
amidinophenyl)oxymethyl)-benz:imidazol-5-yl-carboxylic acid-
N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and
sodium hydroxide solution.
Yield: 82 % of theory,
C26H25N5~4 (471.5)
Rf value: 0.11 (silica gel; dichloromethane/ethanol = 4:1)
EKA mass spectrum: (M+H)+ - 472
(M+H+Na)++ = 247.6
(M+Na)+ - 494
(M+2Na) ++ - 258 . 6
CA 02277949 1999-07-14
- ;B 5 -
Example 56
1-Methyl-2-[2-(2-amidinothiophen-5-yl)ethyl]-benzimidazol-
5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-
ethoxycarbonylethyl)-amide-hydrochloride
a) 1-Methyl-2- f2- (2-cvanothiophen-5 girl) -ethyll -
benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-
ethoxvcarbonylethyl)-amide
Prepared analogously to Example 25c from 3-(2-
~- cyanothiophen-5-yl)-propionic acid and 3-amino-
4-methylamino-benzoic acid-N-(2-pyridyl)-
N-(2-ethoxycarbonylethyl)amid~e.
Yield: 18 % of theory,
Rf value: 0.66 (silica gel; dichloromethane/methanol = 9:1)
b) 1-Methyl-2-f2-(2-amidinothiophen-5-vl)ethvl
benzimidazol-5-yl-carboxylic acid-N- (2 pyridyl) -N- (2-
ethoxycarbonyleth~rl) -amide-hydrochloride
Prepared analogously to Examp:Le 25d from 1-methyl-2-[2-(2-
cyanothiophen-5-yl)ethyl]-ben:aimidazol-5-yl-carboxylic
acid-N- ( 2 -pyridyl ) -N- ( 2 -ethox!~carbonylethyl ) -amide and
ethanolic hydrochloric acid, ethanol and ammonium
,.-.
carbonate.
Yield: 53 % of theory,
C26H28N6~3S (504.6)
Rf value: 0.22 (silica gel; dichloromethane/methanol = 5:1)
EKA mass spectrum: (M+H)+ - 505
3 0 ( M+H+Na ) ++ = 2 6 4
CA 02277949 1999-07-14
- 86 -
Example 57
1-Methyl-2-[2-(2-amidinothiophen-5-yl)ethyl]-benzimidazol-
5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-
hydroxycarbonylethyl)-amide
Prepared analogously to ExamF~le 26 from 1-methyl-2-[2-(2-
amidinothiophen-5-yl)ethyl]-benzimidazol-5-yl-carboxylic
acid-N-(2-pyridyl)-N-(2-ethox:ycarbonylethyl)-amide-
hydrochloride and sodium hydroxide solution.
Yield: 98 % of ,'theory,
'~" C24H24N6~3S (476 . 6 )
EKA mass spectrum: (M+H)+ - 477
(M+Na) + - 499
(M+2H) ++ = 239
Example 58
1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-
5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-
ethoxycarbonylethyl)-amide-hydrochloride
a) 1-Methyl-2- (N- (4-cyano~henyl) -aminomethyll -benzimidazol-
?~ 5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-
ethoxycarboMethyl)-amide
Prepared analogously to Example 25c from N-(4-cyanophenyl)-
glycine and 3-amino-4-methylamino-benzoic acid-N-(2-
pyridyl)-N-(2-ethoxycarbonylethyl)-amide.
Yield: 61 0 of theory,
Rf value: 0.62 (silica gel; dichloromethane/methanol =
19:1)
b) 1-Methyl-2- fN- (4-amidinophenyl) -aminomethyll -
benzimidazol-5-vl-carboxvlic acid-N-(2-pvridvl)-N-(2-
ethoxycarbonvlethyl)-amide-hydrochloride
Prepared analogously to Examp:Le 25d from 1-methyl-2-[N-(4-
cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic
CA 02277949 1999-07-14
- Ei7 -
acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide and
ethanolic hydrochloric acid, ethanol and ammonium
carbonate.
Yield: 71 % of theory,
C27H29N7~3 (499.6)
Rf value: 0.28 (silica gel; di.chloromethane/methanol = 5:1)
EKA mass spectrum: (M+H)+ - 500
( M+H+Na ) ++ = 2 61. 8
(M+2H)++ - 250.8
Example 59
1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-
5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-
hydroxycarbonylethyl)-amide
Prepared analogously to Examp7_e 26 from 1-methyl-2-[N-(4-
amidinophenyl)-aminomethyl]-be~nzimidazol-5-yl-carboxylic
acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-
hydrochloride and sodium hydroxide solution.
Yield: 91 % of theory,
C25H25N7~3 (471.5)
EKA mass spectrum: (M+H)+ - 472
(M+H+Na)++ = 247.6
(M+2H)++ - 236.7
(M+2Na)++ - 258.6
Example 60
1-Methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-
carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-
amide-hydrochloride
a) 1-Methyl-2- [2- (4-cyanophenyl) -ethyll -benzimidazol-5-yl-
carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-
amide
___ ___~___..__._... _____~ CA 02277949 1999-07-14 "~~....
.___._____...____._..
- 88 -
Prepared analogously to Example 149a from 3-(4-
cyanophenyl)-propionic acid wind 3-amino-4-methylamino-
benzoic acid-N-(2-pyridyl)-N-~(2-ethoxycarbonylethyl)-amide.
Yield: 22 % of theory,
Rf value: 0.68 (silica gel; dichloromethane/methanol =
19:1)
b) 1-Methyl-2-f2-(4-amidinophenvl)ethvll-benzimidazol-5-vl-
carboxylic acid-N- ( 2 -Qvrid~rl ) -N- ( 2 -ethoxycarbonylethvl ) -
amide-hvdrochloride
Prepared analogously to Example 25d from 1-methyl-2-[2-(4-
cyanophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-
pyridyl)-N-(2-ethoxycarbonylethyl)-amide and ethanolic
hydrochloric acid, ethanol and ammonium carbonate.
Yield: 85 0 of theory,
C28H30N6~3 (498.6)
Rf value: 0.30 (silica gel; dichloromethane/methanol = 5:1)
EKA mass spectrum: (M+H)+ - 499
( M+H+Na ) ++ = 2 61
Example 61
1-Methyl-2- [2- (4-amidinopheny:l) ethyl] -benzimidazol-5-yl-
~~ carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-
amide
Prepared analogously to Examp:Le 26 from 1-methyl-2-[2-(4
amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N
(2-pyridyl)-N-(2-ethoxycarbon~tlethyl)-amide-hydrochloride
and sodium hydroxide solution..
Yield: 97 % of theory,
C26H26N6~3 (470.5)
EKA mass spectrum: (M+H)+ - 471
( M+H+Na ) ++ = 2 4 7
(M+Na)+ - 493
CA 02277949 1999-07-14
- 89 -
Example 62
1-Methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-
carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-
hydrochloride
Prepared analogously to Example 25d from 1-methyl-2-[2-(4-
cyanophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-
phenyl-N-(2-ethoxycarbonylethyl)-amide and ethanolic
hydrochloric acid, ethanol and ammonium carbonate.
,,~. Yield: 86 % of theory,
C29H31N5~3 (497.6)
Rf value: 0.11 (silica gel; dichloromethane/ethanol = 4:1)
EKA mass spectrum: (M+H)+ - 498
(M+2H)++ = 249.8
Example 63
1-Methyl-2-[2-(4-amidinopheny:L)ethyl]-benzimidazol-5-yl-
carboxylic acid-N-phenyl-N-(2~-hydroxycarbonylethyl)-amide-
hydrochloride
",_", Prepared analogously to Example 26 from 1-methyl-2- [2- (4-
amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-
phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and
sodium hydroxide solution.
Yield: 71 % of theory,
C27H27N5~3 (469.6)
EKA mass spectrum: (M+H)+ - 470
(M+H+Na)++ = 246.6
(M+Na) + - 492
(M+2H)++ - 235.6
_____..... _._. CA 02277949 1999-07-14 ~_. . . ..........___.._.
- :90 -
Example 64
1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-
5-yl-carboxylic acid-N-(2-pyridyl)-N-
(methoxycarbonylmethyl)-amide-dihydrochloride
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-
cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic
acid-N-(2-pyridyl)-N-(methoxycarbonylmethyl)-amide and
methanolic hydrochloric acid, methanol and ammonium
carbonate.
.- Yield: 73 % of theory,
C25H25N7~3 (471.5)
Rt value: 0.12 (silica gel; dichloromethane/ethanol = 4:1)
EKA mass spectrum: (M+H)+ - 472
(M+H+Na)++ = 247.8
Example 65
1-Methyl-2-[N-(4-amidinopheny:L)-aminomethyl]-benzimidazol-
5-yl-carboxylic acid-N-(2-pyr:idyl)-N-(2-
methoxycarbonylethyl)-amide-hydrochloride
,,... Prepared analogously to Example 25d from 1-methyl-2-[N-(4-
cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic
acid-N-(2-pyridyl)-N-(2-metho~cycarbonylethyl)-amide and
methanolic hydrochloric acid, methanol and ammonium
carbonate.
Yield: 78 % of theory,
C26H27N703 (485.6)
Rf value: 0.31 (silica gel; dichloromethane/methanol = 5:1)
EKA mass spectrum: (M+H)+ - 486
(M+H+Na)++ = 254.8
CA 02277949 1999-07-14
_ cal _
Example 66
1-Methyl-2- [2- (4-amidinopheny:l) ethyl] -benzimidazol-5-yl-
carboxylic acid-N-phenyl-N-[2-(1H-tetrazol-5-yl)ethyl]-
amide-hydrochloride
a) 1-Methyl-2-f2-(4-cyanophemrl)ethyll-benzimidazol-5-yl-
carboxylic acid-N=phenyl-N-f2~-(1H-tetrazol-5-vl)ethyll-
amide
Prepared analogously to Example 25c from 3-(4-cyanophenyl)
propionic acid and 3-amino-4-cnethylamino-benzoic acid
,~ N-phenyl-N- [2- (1H-tetrazol-5-yl) ethyl] -amide.
Yield: 67 % of theory,
IR Mass spectrum (KBr): characaeristic bands at
3439.5 cm-1 (N-H); 2235.5 cm-1
C=N ) ;
1631.E~ cm-1 (C=O)
b) 1-Methyl-2-f2-(4-amidinophEnvl)ethyl]-benzimidazol-5-vl-
carboxylic acid-N-phenyl-N-f2-(1H-tetrazol-5-yl)ethyll-
amide-hydrochloride
Prepared analogously to Example 25d from 1-methyl-2-[2-(4-
cyanophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-
phenyl-N-[2-(1H-tetrazol-5-yl)ethyl]-amide and ethanolic
-,
hydrochloric acid, ethanol and. ammonium carbonate.
Yield: 92 % of theory,
C27H27N90 (493.6)
EKA mass spectrum: (M+H)+ - 494
(M+Na)+ - 516
(M+2H) ++ = 258 . 7
CA 02277949 1999-07-14
- 92 -
Example 67
1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-
5-yl-carboxylic acid-N-phenyl.-N-[2-(1H-tetrazol-5-
yl)ethyl)-amide-hydrochloride:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-
cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic
acid-N-phenyl-N-[2-(1H-tetraz;ol-5-yl)ethyl]-amide and
ethanolic hydrochloric acid, ethanol and ammonium
carbonate.
,,,.~ Yield: 29 % of theory,
C26H26N10~ (494.6)
EKA mass spectrum: (M+H}+ = 495
Example 68
1-Methyl-2-[N-(4-amidinophenyl}-aminomethyl]-benzimidazol-
5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-n-
hexyloxycarbonylethyl)-amide-hydrochloride
0.60 g (1.1 mMol) of 1-methyl-2-[N-(4-amidinophenyl)-
aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-
pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride were
added to about 30 ml of n-hexanol saturated with hydrogen
chloride and the mixture was stirred for 19 hours at room
temperature. Then the hexano:l was distilled off in vacuo,
the residue was mixed with about 5 ml of 1N ammonia
solution with stirring and evaporated down once more. The
crude product thus obtained w;as purified by column
chromatography (silica gel, d:ichloromethane/methanol =
5:1) .
Yield: 53 0 of theory,
C31H37N7~3 (555.7)
Rf value: 0.36 (silica gel; di.chloromethane/methanol
- 5:1 )
i
CA 02277949 1999-07-14
_ c~3 _
EKA mass spectrum: (M+H)+ = 556
Example 69
1-Methyl-2- [N- (4-amidinopheny:l) -N-methyl-aminomethyl] -
benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-
ethoxycarbonylethyl)-amide-hydrochloride
a) 1-Methyl-2- [N- (4-cyanophenyl) -N-methyl-aminomethyl] -
benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-
ethoxycarbonylethyl)-amide
Prepared analogously to Examp:Le 25c from N-(4-cyanophenyl)-
N-methylglycine and 3-amino-4--methylamino-benzoic acid-N-
(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide.
Yield: 71 % of theory,
Rf value: 0.66 (silica gel; dichloromethane/methanol =
19:1)
b) 1-Methyl-2- [N- (4-amidinophenyl) -N-methyl-aminomethyl] -
benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-
ethoxycarbonvlethYl)-amide-hydrochloride
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-
cyanophenyl)-N-methyl-aminomet.hyl]-benzimidazol-5-yl-
carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-
,,~..
amide and ethanolic hydrochloric acid, ethanol and ammonium
carbonate.
Yield: 77 % of theory,
C28H31N7~3 (513.6)
EKA mass spectrum: (M+H)+ - 514
(M+H+Na)++ = 268.7
CA 02277949 1999-07-14
- 94 -
Example 70
1-Methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-
benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-
hydroxycarbonylethyl)-amide
Prepared analogously to Example 26 from 1-methyl-2-[N-(4-
amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-
carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-
amide-hydrochloride and sodium hydroxide solution.
Yield: 66 % of~theory,
C26H27N7~3 (485.6)
EKA mass spectrum: (M+H)+ - 486
(M+Na) + - 508
(M+2Na)++ = 265.6
Example 71
1-Methyl-2- [2- (4-amidinopheny:l) ethyl] -benzimidazol-5-yl
carboxylic acid-N-cyclopentyl-N-(2-ethoxycarbonylethyl)
amide-hydrochloride
Prepared analogously to Examp:Le 25d from 1-methyl-2-[2-(4-
.-- cyanophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-
cyclopentyl-N-(2-ethoxycarbonylethyl)-amide and ethanolic
hydrochloric acid, ethanol and ammonium carbonate.
Yield: 65 % of theory,
C28H35N503 (489.6)
EKA mass spectrum: (M+H)+ = 490
CA 02277949 1999-07-14
- 95 -
Example 72
1-Methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-
carboxylic acid-N-cyclopentyl-N-(2-hydroxycarbonylethyl)-
amide
Prepared analogously to Example 26 from 1-methyl-2-[2-(4
amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N
cyclopentyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride
and sodium hydroxide solution.
Yield: 89 0 of theory,
"' C26H31N5~3 (461. 6 )
EKA mass spectrum: (M+H)+ - 462
( M+H+Na ) ++ = 2 4 2 . 6
(M+Na)+ - 484
(M+2H)++ - 231.6
Example 73
1-Methyl-2-[N-(4-amidinopheny:L)-aminomethyl]-benzimidazol-
5-yl-carboxylic acid-N-cyclopentyl-N-(2-
ethoxycarbonylethyl)-amide-hydrochloride
''"' Prepared analogously to Examp:Le 25d from 1-methyl-2- [N- (4-
cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic
acid-N-cyclopentyl-N-(2-ethox;rcarbonylethyl)-amide and
ethanolic hydrochloric acid, eahanol and ammonium
carbonate.
Yield: 60 % of theory,
C27H34N6~3 (490.6)
EKA mass spectrum: (M+H)+ = 491
CA 02277949 1999-07-14
Examt~le 74
1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-
5-yl-carboxylic acid-N-cyclopentyl-N-(2-
hydroxycarbonylethyl)-amide
Prepared analogously to Example 26 from 1-methyl-2-[N-(4-
amidinophenyl)-aminomethyl]-b~enzimidazol-5-yl-carboxylic
acid-N-cyclopentyl-N-(2-ethoxycarbonylethyl)-amide-
hydrochloride and sodium hydroxide solution.
Yield: 45 % of ,'theory,
C25H30N3~4 (462.6)
EKA mass spectrum: (M+H)+ - 463
(M+H+Na)++ = 243
(M+Na) + - 485
(M+2Na) ++ - 254
Example 75
1-Methyl-2-[N-(4-amidinopheny7:)-N-methyl-aminomethyl]-
benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-
(ethoxycarbonylmethyl)-amide-hydrochloride
Prepared analogously to Examp7.e 25d from 1-methyl-2-[N-(4-
cyanophenyl)-N-methyl-aminomet:hyl]-benzimidazol-5-yl-
carboxylic acid-N-(2-pyridyl)-~N-(ethoxycarbonylmethyl)-
amide and ethanolic hydrochloric acid, ethanol and ammonium
carbonate.
Yield: 54 % of theory,
C27H2gN703 (499.6)
EKA mass spectrum: (M+H) + -. 500
(M+2H )++ _- 250.7
CA 02277949 1999-07-14
Example 76
1-Methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-
benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-
(hydroxycarbonylmethyl)-amide
Prepared analogously to Example 26 from 1-methyl-2-[N-(4-
amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-
carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-
amide-hydrochloride and sodium hydroxide solution.
Yield: 68 % of theory,
~~ C25H25N703 (471.5)
EKA mass spectrum: (M+H)+ -- 472
(M+Na) + -- 494
(M+2Na) ++ _- 258 . 6
Example 77
1-Methyl-2-[2-(4-amidinopheny7_)-ethyl]-benzimidazol-5-yl-
carboxylic acid-N-(3-pyridyl)--N-(2-ethoxycarbonylethyl)-
amide-hydrochloride
Prepared analogously to Exampl-a 25d from 1-methyl-2- [2- (4-
.- cyanophenyl)-ethyl]-benzimida2:o1-5-yl-carboxylic acid-N-(3-
pyridyl)-N-(2-ethoxycarbonylet:hyl)-amide and ethanolic
hydrochloric acid, ethanol anct ammonium carbonate.
Yield: 91 % of theory,
C28H30N6~3 (498.6)
Rf value: 0.19 (silica gel; di~~hloromethane/ethanol = 4:1)
EKA mass spectrum: (M+H)+ - 499
___._______._____... ____________CA-02277949 1999-07-14 --________. _ .
- 98 -
Example 78
1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-
5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-
ethoxycarbonylethyl)-amide-dihydrochloride
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-
cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic
acid-N-(3-pyridyl)-N-(2-ethoxycarbonylethyl)-amide and
ethanolic hydrochloric acid, ethanol and ammonium
carbonate. ,'
Yield: 86 % of theory,
C27H29N7~3 (499.6)
Rf value: 0.09 (silica gel; dichloromethane/ethanol = 4:1 )
EKA mass spectrum: (M+H)+ = 500
Example 79
1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-
5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-
hydroxycarbonylethyl)-amide
Prepared analogously to Example 26 from 1-methyl-2-[N-(4-
-. amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic
acid-N-(3-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-
dihydrochloride and sodium hydroxide solution.
Yield: 85 % of theory,
C25H25N7~3 (471.5)
EKA mass spectrum: (M+H)+ - 472
(M+2H)++ - 236.6
(M+2Na)++ = 258.6
CA 02277949 1999-07-14
_ c~9 _
Example 80
1-Methyl-2- [N- (4-amidinopheny:l) -N-methyl-aminomethyl] -
benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-
ethoxycarbonylethyl)-amide-hydrochloride
Prepared analogously to Examp:Le 25d from 1-Methyl-2-[N-(4-
cyanophenyl)-N-methyl-aminomei=hyl]-benzimidazol-5-yl-
carboxylic acid-N-(3-pyridyl)~-N-(2-ethoxycarbonylethyl)-
amide and ethanolic hydrochloric acid, ethanol and ammonium
carbonate.
Yield: 64 % of theory,
C28H31N7~3 (513.6)
EKA mass spectrum: (M+H) + = 57_4
Example 81
1-Methyl-2-[N-(4-amidinophenyl_)-N-methyl-aminomethyl]-
benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-
hydroxycarbonylethyl)-amide
Prepared analogously to Example 26 from 1-Methyl-2-[N-(4-
amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-
carboxylic acid-N-(3-pyridyl)-N-(2-ethoxycarbonylethyl)-
'~ 25 amide-hydrochloride and sodium hydroxide solution.
Yield: 70 % of theory,
C26H27N703 (485.6)
EKA mass spectrum: (M+H)+ - 486
(M+Na)+ - 508
(M+2Na)++ = 265.6
CA 02277949 1999-07-14
- :L00 -
Example 82
1-Methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-
benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-
ethoxycarbonylethyl)-amide-h~~drochloride
a) 1-Methyl-2-fN-(4-cyanopherwl)-N-methyl-aminomethyll-
benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-pvridvl)-N-
(2-ethoxycarbonylethyl) -amide:
Prepared analogously to Example 25c from N-(4-cyanophenyl)
N-methylglycine and 3-amino-4-methylamino-benzoic acid
,~ N-phenyl-N-(2-ethoxycarbonylethyl)-amide.
Yield: 71 °s of theory,
Rf value: 0.38 (silica gel; d:ichloromethane/methanol =
19 :1 )
b) 1-Methyl-2-fN-(4-amidinophenvl)-N-methyl-aminomethvl
benzimidazol-5-vl-carboxylic acid-N-phenyl-N-(2-
ethoxycarbonylethvl)-amide-hydrochloride
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-
cyanophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-
carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide
and ethanolic hydrochloric acid, ethanol and ammonium
carbonate.
Yield: 74 % of theory,
C29H32N6~3 (512.6)
EKA mass spectrum: (M+H)+ - 513
( M+H+Na ) ++ = 2 6 8
(M+2H) ++ - 257
CA 02277949 1999-07-14
- 101 -
Example 83
1-Methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-
benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-
hydroxycarbonylethyl)-amide
Prepared analogously to Example 26 from 1-methyl-2-[N-(4-
amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-
carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-
hydrochloride and sodium hydroxide solution.
Yield: 80 % of theory,
C27H28N6~3 (484.6)
EKA mass spectrum: (M+H)+ - 485
(M+H+Na) ++ = 254
(M+Na) + - 507
(M+2Na) + - 265
Example 84
1-ethyl-2-[N-(4-amidinophenyl;I-aminomethyl]-benzimidazol-5-
yl-carboxylic acid-N-(2-pyrid~girl)-N-(2-ethoxycarbonylethyl)-
amide-hydrochloride
Prepared analogously to Example 25d from 1-ethyl-2-[N-(4-
cyanophenyl)-aminomethyl]-ben::imidazol-5-yl-carboxylic
acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide and
ethanolic hydrochloric acid, eahanol and ammonium
carbonate.
Yield: 85 % of theory,
C28H31N703 (513.6)
Rf value: 0.21 (silica gel; dichloromethane/methanol = 5:1)
EKA mass spectrum: (M+H)+ - 514
(M+H+Na)++ = 268.6
(M+2H)++ - 257.7
CA 02277949 1999-07-14
- :L02 -
Example 85
1-ethyl-2-[N-(4-amidinopheny7_)-aminomethyl]-benzimidazol-5-
yl-carboxylic acid-N-(2-pyridyl)-N-(2-
hydroxycarbonylethyl)-amide
Prepared analogously to Example 26 from 1-ethyl-2-[N-(4
amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic
acid-N-(2-pyridyl)-N-(2-etho~sycarbonylethyl)-amide
hydrochloride end 2N sodium hydroxide solution.
.....~. Yield: 49 % of theory,
C26H27N703 (485.6)
EKA mass spectrum: (M+H)+ - 486
(M+H+Na)++ = 254.6
(M+2H) ++ - 243 . 6
(M+2Na) ++ - 265 . 7
Example 86
1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-
5-yl-carboxylic acid-N-(2-fluorophenyl)-N-(2-
ethoxycarbonylethyl)-amide-hydrochloride
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-
cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic
acid-N-(2-fluorophenyl)-N-(2-~ethoxycarbonylethyl)-amide and
ethanolic hydrochloric acid, ~=thanol and ammonium
carbonate.
Yield: 88 % of theory,
C28H2gFN603 (516.6)
Rf value: 0.08 (silica gel; di.chloromethane/ethanol = 4:1)
EKA mass spectrum: (M+H)+ - 517
( M+H+Na ) ++ = 2 7 0
(M+2H) ++ - 259
CA 02277949 1999-07-14
- 103 -
Example 87
1-Methyl-2-[N-(4-amidinopheny:l)-aminomethyl]-benzimidazol-
5-yl-carboxylic acid-N-(2-fluorophenyl)-N-(2-
hydroxycarbonylethyl)-amide
Prepared analogously to Examp:Le 26 from 1-methyl-2-[N-(4-
amidinophenyl)-aminomethyl]-be~nzimidazol-5-yl-carboxylic
acid-N-(2-fluorophenyl)-N-(2-eahoxycarbonylethyl)-amide-
..-. hydrochloride and sodium hydroxide solution.
Yield: 45 % of theory,
C26H25F'N6~3 (488.5)
Rf value: 0.05 (silica gel; dichloromethane/ethanol = 4:1;
EKA mass spectrum: (M+H)+ - 489
( M+H+Na ) ++ = 2 6 7
(M+2H)++ - 256
Example 88
1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-
5-yl-carboxylic acid-N-(3-meth.ylphenyl)-N-(2-
.~- ethoxycarbonylethyl)-amide-hydrochloride
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-
cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic
acid-N-(3-methylphenyl)-N-(2-ethoxycarbonylethyl)-amide and
ethanolic hydrochloric acid, ethanol and ammonium
carbonate.
Yield: 79 % of theory,
C29H32N603 (512.6)
Rf value: 0.10 (silica gel; dic:hloromethane/ethanol = 4:1)
EKA mass spectrum: (M+H)+ - 513
3 5 ( M+H+Na ) ++ :- 2 6 8
CA 02277949 1999-07-1.4'
- :L04 -
Example 89
1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-
5-yl-carboxylic acid-N- (3-met:hylphenyl) -N- (2-
hydroxycarbonylethyl)-amide
Prepared analogously to Exams>le 26 from 1-methyl-2-[N-(4-
amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic
acid-N-(3-methylphenyl)-N-(2-ethoxycarbonylethyl)-amide-
hydrochloride and sodium hydroxide solution.
Yield: 62 % of theory,
,.~.,. C27H28N6~3 (484.6)
EKA mass spectrum: (M+H)+ - 485
( M+H+Na ) ++ = 2 5 4
(M+Na) + - 507
(M+2Na)++ - 265
Example 90
1-Methyl-2- [N- [4- (N-n-hexyloxycarbonylamidino) phenyl] -
aminomethyl]-benzimidazol-5-y:l-carboxylic acid-N-phenyl-N-
(2-ethoxycarbonylethyl)-amide
-- 1.1 g (2. 06 mMol) of 1-methyl-2- [N- (4-amidinophenyl) -
aminomethyl]-benzimidazol-5-y:L-carboxylic acid-N-phenyl-N-
(2-ethoxycarbonylethyl)-amide-hydrochloride was dissolved
in a mixture of 40 ml of tetrahydrofuran and 10 ml of
water, then 570 mg (4.12 mMol) of potassium carbonate and
362 mg (2.2 mMol) of n-hexyl chloroformate were added and
stirred for two hours at room temperature. The solvent was
then distilled off, the residue was mixed with about 50 ml
of saturated saline solution and the resulting solution was
extracted three times with 20 ml of dichloromethane. The
extracts were dried over sodium sulphate and evaporated
down. The crude product thus obtained was purified by
column chromatography (100 g silica gel; dichloromethane +
5% ethanol).
CA 02277949 1999-07-14
- T_05 -
Yield: 78 % of theory,
C35H42N6~5 (626.8)
Rf value: 0.49 (silica gel; dichloromethane/ethanol = 19:1)
EKA mass spectrum: (M+H)+ - 627
(M+H+Na) +~~ - 325
(M+2H)++ - 314
Example 91
1-Methyl-2-[N-[4-(N-methoxycarbonylamidino)phenyl]-amino-
methyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-
ethoxycarbonylethyl)-amide
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-
amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic
acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride
and methyl chloroformate.
Yield: 41 % of theory,
C30H32N6~5 (556.6)
Rf value: 0.85 (silica gel; dichloromethane/ethanol = 4:1)
EKA mass spectrum: (M+H)+ - 557
( M+H+Na ) ++ = 2 9 0
... (M+Na) + - 579
Example 92
1-Methyl-2- [N- [4- (N-ethoxycarbonylamidino) phenyl] -
aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-
(2-methoxycarbonylethyl)-amide
Prepared analogously to Examp7Le 90 from 1-methyl-2-[N-(4-
amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic
acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide-
hydrochloride and ethyl chloroformate.
Yield: 62 % of theory,
C30H32N6~5 (556.6)
.~ ~."-CA 02277949 1999-07-14 ~ -
- 7_06 -
Rf value: 0.51 (silica gel; dichloromethane/ethanol = 19:1)
EKA mass spectrum: (M+H)+ - 557
( M+H+Na ) +~~ - 2 9 0
(M+2H)++ - 279
Example 93
1-Methyl-2-[N-[4-(N-cyclohexyloxycarbonylamidino)phenyl]-
aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-
(2-methoxycarbonylethyl)-amide
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-
amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic
acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide-
hydrochloride and cyclohexyl chloroformate.
Yield: 25 % of theory,
C34H38N6~5 (610.7)
Rf value: 0.44 (silica gel; dichloromethane/ethanol = 19:1)
EKA mass spectrum: (M+H)+ - 611
(M+2H)++ = 306
Example 94
1-Methyl-2- [N- [4- [N- [2- (methy:Lsulphonyl) ethyloxycarbonyl] -
amidino]phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic
acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide
Prepared analogously to Examp:Le 90 from 1-methyl-2-[N-(4-
amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic
acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride
and 2-(methylsulphonyl)-ethyl chloroformate.
Yield: 66 % of theory,
C32H36N607S (648.8)
Rf value: 0.44 (silica gel; dichloromethane/ethanol = 19:1)
EKA mass spectrum: (M+H)+ - 649
( M+H+Na ) ++ = 3 3 6
CA 02277949 1999-07-14
- 107 -
(M+2H) ++ - 325
Example 95
1-Methyl-2-[N-[4-(N-n-octyloxycarbonylamidino)phenyl]-
aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-
(2-methoxycarbonylethyl)-amide
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-
amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic
acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide-
hydrochloride and n-octyl chloroformate.
Yield: 41 % of theory,
C36H44N6~5 (640.8)
Rf value: 0.43 (silica gel; dichloromethane/ethanol = 19:1)
EKA mass spectrum: (M+H)+ - 641
( M+Na ) + _ ~6 6 3
Example 96
1-Methyl-2- [N- [4- (N-hydroxylamidino) phenyl] -aminomethyl] -
benzimidazol-5-yl-carboxylic <~cid-N-phenyl-N-(2-
ethoxycarbonylethyl)-amide
1.44 g (3. 0 mMol) of 1-methyl-2- [N- (4-cyanophenyl) -
aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-
(2-ethoxycarbonylethyl)-amide,, 0.625 g (9.0 mMol) of
hydroxylamine hydrochloride and 0.425 g (4.0 mMol) of
sodium carbonate were dissolve=d in 80 ml of ethanol and
refluxed for 7 hours. Then a further 210 mg of
hydroxylamine hydrochloride and 170 mg of sodium carbonate
were added, the mixture was boiled for a further 5 hours
and then evaporated down in v~acuo. The residue was
dissolved in about 30 ml of dichloromethane, the solution
obtained was washed with 20 m7_ of water, the organic phase
was dried and evaporated down. The crude product thus
_______... ... .. __________,___ CA 02277949 1999-07-14 .- __...
- 7_08 -
obtained was purified by column chromatography (200 g
silica gel, dichloromethane -~- 4% ethanol).
Yield: 39 % of theory,
C28H30N6~4 (514.6)
Rf value: 0.15 (silica gel; dichloromethane/ethanol = 19:1)
EKA mass spectrum: (M+H)+ -. 515
(M+Na)+ -. 537
(2M+H)+ - 1029
(2M+Na) + = 1051
.--. Exampl a 9 7
1-Methyl-2-[N-[4-(N-n-heptyloxycarbonylamidino)phenyl]-
aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-
(2-methoxycarbonylethyl)-amide
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-
amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic
acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide-
hydrochloride and n-heptyl chloroformate.
Yield: 43 % of theory,
C35H42N6~5 (626.8)
Rf value: 0.40 (silica gel; dichloromethane/ethanol = 19:1)
EKA mass spectrum: (M+H)+ - 627
2 5 ( M+H+Na ) ++ = 3 2 5
(M+Na)+ - 649
Example 98
1-Methyl-2- [N- [4- (N-benzoylam:idino) phenyl] -aminomethyl] -
benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-
methoxycarbonylethyl)-amide
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-
amidinophenyl)-aminomethyl]-be_nzimidazol-5-yl-carboxylic
CA 02277949 1999-07-14
- 7_09 -
acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide-
hydrochloride and benzoyl chloride.
Yield: 88 % of theory,
C34H32N604 (588.7)
Rf value: 0.37 (silica gel; dichloromethane/ethanol = 19:1)
1H-NMR spectrum (D6-DMSO): 2.61 (t,2H), 3.54 (s,3H), 3.76
(s,3H), 4.10 (t,2H), 4.61 (d,2H), 6.83 (d,2H), 7.05 to 7.55
(m,l2H),8.03 (d,2H), 8.25 (dd.,2H), 8.98 (s,lH), 10.48
(s, 1H)
Example 99
1-Methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino)phenyl]-
aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-
(2-methoxycarbonylethyl)-amide
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-
amidinophenyl)-aminomethyl]-b~~nzimidazol-5-yl-carboxylic
acid-N-phenyl-N-(2-methoxycar7nonylethyl)-amide-
hydrochloride and n-hexyl chloroformate.
Yield: 54 % of theory,
C34H40N605 (612.7)
Rf value: 0.45 (silica gel; dichloromethane/ethanol = 19:1)
.~..
EKA mass spectrum: (M+H)+ - 613
Example 100
1-Methyl-2- [N- [4- (N-n-hexyloxycarbonylamidino) phenyl] -
aminomethyl]-benzimidazol-5-y7.-carboxylic acid-N-phenyl-N-
(2-n-propyloxycarbonylethyl)-amide
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-
amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic
acid-N-phenyl-N-(2-n-propyloxycarbonylethyl)-amide-
hydrochloride and n-hexyl chlc>roformate.
Yield: 31 % of theory,
CA 02277949 1999-07-14 ~ -
- :L 10 -
C36H44N6~5 (640.8)
Rf value: 0.42 (silica gel; dichloromethane/ethanol = 19:1)
EKA mass spectrum: (M+H)+ - 641
(M+H+Na) +i- - 332
(M+Na) + - 663
Example 101
1-Methyl-2- [N- [4- (N-ethoxycarbonylamidino) phenyl] -
aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-
pyridyl)-N-(2-methoxycarbonylethyl)-amide
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-
amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic
acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide-
hydrochloride and ethyl chloroformate.
Yield: 72 % of theory,
C29H31N7~5 (557.6)
Rf value: 0.58 (silica gel; dichloromethane/methanol =
9:1)
EKA mass spectrum: (M+H)+ - 558
(M+H+Na)++ = 290.8
(M+Na) + - 580
Example 102
1-Methyl-2- [N- [4- (N-n-octylox;rcarbonylamidino) phenyl] -
aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-
pyridyl)-N-(2-methoxycarbonylethyl)-amide
Prepared analogously to Examp]_e 90 from 1-methyl-2-[N-(4-
amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic
acid-N-(2-pyridyl)-N-(2-metho~:ycarbonylethyl)-amide-
hydrochloride and n-octyl chloroformate.
Yield: 57 % of theory,
C35H43N705 (641.8)
CA 02277949 1999-07-14
- 1:11 -
Rf value: 0.60 (silica gel; di.chloromethane/methanol = 9:1)
EKA mass spectrum: (M+H)+ - 642
(M+H+Na)++ = 332.8
(M+Na) + - 664
_._ .._____.___. . ... _._._______CA.O2277949 1999-07-14 ''-w°_.______
._____.__.__._____..
- :L 12 -
Example 103
1-Methyl-2- [N- [4- (N-methoxycarbonylamidino) phenyl] -amino-
methyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-
N-(2-ethoxycarbonylethyl)-amide
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-
amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic
acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-
hydrochloride and methyl chloroformate.
Yield: 48 0 of,'theory,
~ C29H31N705 (557.6)
Rf value: 0.62 (silica gel; d:ichloromethane/methanol = 9:1)
EKA mass spectrum: (M+H)+ - 558
(M+H+Na)++ = 290.7
(M+Na) + - 580
Example 104
1-Methyl-2-[N-[4-(N-n-octyloxycarbonylamidino)phenyl]-
aminomethyl)-benzimidazol-5-yl-carboxylic acid-N-(2-
pyridyl)-N-(2-hydroxycarbonylethyl)-amide
0.7 g (1.l mMol) of 1-methyl-2- [N- [4- (N-n-
octyloxycarbonylamidino)-phenyl]-aminomethyl]-benzimidazol-
5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-
methoxycarbonylethyl)-amide was stirred in a mixture of
0.12 g (3.0 mMol) of sodium hydroxide, 5 ml of water and
10 ml of methanol for one hour at room temperature. Then
the mixture was diluted with 20 ml of water and adjusted to
pH 6 with glacial acetic acid. Then about 5 ml of
diethylether were added and tlhe mixture was vigourously
stirred for one hour. The product thus precipitated was
suction filtered, washed with a little water, then with
diethylether and dried.
Yield: 80 0 of theory,
CA 02277949 1999-07-14
- 113 -
C34H41N7~5 (627.8)
EKA mass spectrum: (M+H)+ - 628
(M+H+Na)++ = 325.7
(M+Na)+ - 650
(M+2Na) ++ - 337 . 7
Example 105
1-Methyl-2- [N- [4- [N- (2-methyl;~ulphonyl-
ethyloxycarbonyl)amidino]-phenyl]-aminomethyl]-
,~-- benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -
N-(2-ethoxycarbonylethyl)-amide
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-
amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic
acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-
hydrochloride and 2-(methylsul.phonyl)-ethyl chloroformate.
Yield: 65 % of theory,
C31H35N707S (649.7)
Rf value: 0.54 (silica gel; dichloromethane/methanol = 9:1)
EKA mass spectrum: (M+H)+ - 650
( M+H+Na ) ++ = 3 3 6 . 6
~~ (M+Na)+ - 672
(M+2Na) ++ - 347 . 6
Example 106
1-Methyl-2-[N-[4-(N-n-butyloxycarbonylamidino)phenyl]-
aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-
pyridyl)-N-(2-methoxycarbonylethyl)-amide
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-
amidinophenyl)-aminomethyl]-be:nzimidazol-5-yl-carboxylic
acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide-
hydrochloride and n-butyl chlo:roformate.
.__......_........ ..__...~~CA 02277949 1999-07-14 ___. _.__... ..
- 114 -
Yield: 30 % of theory,
C31H35N705 (585.7)
Rf value: 0.62 (silica gel; d:ichloromethane/methanol = 9:1)
EKA mass spectrum: (M+H)+ - 586
( M+H+Na ) ++ = 3 0 4 . 7
(M+2H) ++ - 293 . 7
Example 107
1-Methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino)phenyl]-
aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-
pyridyl)-N-(2-methoxycarbonylethyl)-amide
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-
amidinophenyl)-aminomethyl]-b~enzimidazol-5-yl-carboxylic
acid-N-(2-pyridyl)-N-(2-metho:xycarbonylethyl)-amide-
hydrochloride and n-hexyl chloroformate.
Yield: 51 % of theory,
c33H39N7~5 (613.7)
Rf value: 0.56 (silica gel; di.chloromethane/methanol - 9:1)
EKA mass spectrum: (M+H)+ - 614
(M+H+Na)++ = 318.7
(M+2H) ++ - 307. 6
Example 108
1-Methyl-2- [N- [4- (N-n-heptylo:~ycarbonylamidino) -phenyl] -
aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-
pyridyl)-N-(2-methoxycarbonylesthyl)-amide
Prepared analogously to Examp~~'_e 90 from 1-methyl-2-[N-(4-
amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic
acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide-
hydrochloride and n-heptyl ch7_oroformate.
Yield: 21 0 of theory,
C34H41N7~5 (627.8)
CA 02277949 1999-07-14
- :L15 -
Rf value: 0.60 (silica gel; dichloromethane/methanol = 9:1)
EKA mass spectrum: (M+H)+ - 628
( M+H+Na ) +i- - 3 2 5 . 7
(M+2H)++ - 314.7
Example 109
1-Methyl-2-(N-[4-(N-n-pentyloxycarbonylamidino)-phenyl]-
aminomethyl)-benzimidazol-5-yl-carboxylic acid-N-(2-
pyridyl)-N-(2-methoxycarbonylethyl)-amide
,~
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-
amidinophenyl)-aminomethyl)-b~enzimidazol-5-yl-carboxylic
acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide-
hydrochloride and n-pentyl chloroformate.
Yield: 66 % of theory,
C32H37N7~5 (599.7)
Rf value: 0.58 (silica gel; dichloromethane/methanol = 9:1)
EKA mass spectrum: (M+H)+ - 600
(M+H+Na)++ = 311.7
(M+Na)+ - 622
Example 110
1-Methyl-2- [N- [4- (N-n-nonyloxycarbonylamidino) phenyl) -
aminomethyl]-benzimidazol-5-y:l-carboxylic acid-N-(2-
pyridyl)-N-(2-methoxycarbonylethyl)-amide
Prepared analogously to Examp:Le 90 from 1-methyl-2-[N-(4-
amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic
acid-N-(2-pyridyl)-N-(2-methoacycarbonylethyl)-amide-
hydrochloride and n-nonyl chloroformate.
Yield: 60 0 of theory,
C36H45N7~5 (655.8)
Rf value: 0.48 (silica gel; dichloromethane/methanol = 9:1)
EKA mass spectrum: (M+H)+ - 656
Image CA 02277949 1999-07-14
- 117 -
Example 111
1-Methyl-2-[N-[4-(N-benzoylamidino)phenyl]-aminomethyl]-
benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-
methoxycarbonylethyl)-amide
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-
amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic
acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide-
hydrochloride and benzoyl chloride.
Yield: 62 % of theory,
C33H31N7~4 (589.7)
Rf value: 0.50 (silica gel; d:ichloromethane/methanol = 9:1)
EKA mass spectrum: (M+H)+ - 590
(M+Na)+ = 612
Example 112
1-Methyl-2-[N-[4-(N-nicotinoylamidino)phenyl]aminomethyl]-
benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-
methoxycarbonylethyl)-amide
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-
amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic
acid-N-(2-pyridyl)-N-(2-metho:xycarbonylethyl)-amide-
hydrochloride and nicotinic acid chloride.
Yield: 40 % of theory,
C32H30N8~4 (590.7)
Rf value: 0.47 (silica gel; di.chloromethane/methanol = 9:1)
EKA mass spectrum: (M+H)+ - 591
( M+H+Na ) ++ = 3 0 7
( M+Na ) + - 613
'~ ~'~ CA 02277949 1999-07-14
- 118 -
Example 113
1-Methyl-2- [N- [4- (N-n-hexylo:xycarbonylamidino)phenyl] -
aminomethyl]-benzimidazol-5-:yl-carboxylic acid-N-(2-
pyridyl)-N-(2-ethoxycarbonylethyl)-amide
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-
amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic
acid-N-(2-pyridyl)-N-(2-etho~cycarbonylethyl)-amide-
hydrochloride and n-hexyl chloroformate.
Yield: 51 % of,theory,
C34H41N7~5 (627.8)
Rf value: 0.53 (silica gel; dichloromethane/methanol = 9:1)
EKA mass spectrum: (M+H)+ - 628
( M+H+Na ) + ~- - 3 2 5 . 7
(M+2H) ++ - 314 . 7
Example 114
1-Methyl-2-[N-[4-(N-n-octyloxycarbonylamidino)phenyl]-
aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-
pyridyl)-N-(2-ethoxycarbonylethyl)-amide
Prepared analogously to Example 90 from l-methyl-2-[N-(4-
amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic
acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-
hydrochloride and n-octyl chloroformate.
Yield: 57 % of theory,
C36H45N7~5 (655.8)
Rf value: 0.46 (silica gel; dichloromethane/methanol
- 9:1 )
EKA mass spectrum: (M+H)+ - 656
(M+H+Na)++ = 339.7
(M+2H)++ - 328.7
CA 02277949 1999-07-14
- 119 -
Example 115
1-Methyl-2- (N- [4- [N- (2-methylsulphonyl-
ethyloxycarbonyl)amidino]-phenyl]-aminomethyl]-
benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-
ethoxycarbonylmethyl-amide
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-
amidinophenyl)-aminomethyl]-b~enzimidazol-5-yl-carboxylic
acid-N-(2-pyridyl)-N-ethoxyca:rbonylmethyl-amide-
hydrochloride and 2-(methylsu:lphonyl)-ethyl chloroformate.
'" Yield: 72 % of theory,
C30H33N707S (635.7)
Rf value: 0.23 (silica gel; di.chloromethane/ethanol = 19:1)
EKA mass spectrum: (M+H)+ - 636
(M+H+Na)++ = 329.8
Example 116
1-Methyl-2- (N- [4- (N-cyclohexy7_oxycarbonylamidino) -
phenyl]aminomethyl]-benzimida::ol-5-yl-carboxylic acid-N-(2-
pyridyl)-N-methoxycarbonylmethyl-amide
Prepared analogously to Examp].e 90 from 1-methyl-2-[N-(4-
amidinophenyl)-aminomethyl]-be~nzimidazol-5-yl-carboxylic
acid-N-(2-pyridyl)-N-methoxycarbonylmethyl-amide-
hydrochloride and cyclohexyl chloroformate.
Yield: 40 % of theory,
C32H35N7~5 (597.7)
Rf value: 0.26 (silica gel; di~~hloromethane/ethanol = 19:1)
EKA mass spectrum: (M+H)+ - 598
(M+Na)+ = 620
CA 02277949 1999-07-14~
-1~'.0-
Example 117
1-Methyl-2-[N-[4-(N-methoxycarbonylamidino)-phenyl]
aminomethyl]-benzimidazol-5-y7.-carboxylic acid-N-(2
pyridyl)-N-ethoxycarbonylmethyl-amide
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-
amidinophenyl)-aminomethyl]-be:nzimidazol-5-yl-carboxylic
acid-N-(2-pyridyl)-N-ethoxycarbonylmethyl-amide-
hydrochloride and methyl chloroformate.
Yield: 62 % of theory,
C2gH29N7~5 (543.6)
Rf value: 0.19 (silica gel; dichloromethane/ethanol = 19:1)
EKA mass spectrum: (M+H)+ - 544
(M+H+Na)++ = 283.8
(M+Na) + - 566
Example 118
1-Methyl-2- [N- [4- (N-ethoxycarbonylamidino) -phenyl] -amino-
methyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-
methoxycarbonylmethyl-amide
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-
amidinophenyl)-aminomethyl]-be;nzimidazol-5-yl-carboxylic
acid-N-(2-pyridyl)-N-methoxycarbonylmethyl-amide-
hydrochloride and ethyl chloroformate.
Yield: 42 % of theory,
C28H29N7~5 (543.6)
Rf value: 0.20 (silica gel; dichloromethane/ethanol = 19:1)
EKA mass spectrum: (M+H)+ = 544
CA 02277949 1999-07-14
- 1.21 -
Example 119
1-Methyl-2- [N- [4- (N-n-octylox:ycarbonyl-amidino) -
phenyl]aminomethyl)-benzimida.zol-5-yl-carboxylic acid-N-(3-
pyridyl)-N-(2-ethoxycarbonylethyl)-amide
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-
amidinophenyl)-aminomethyl)-benzimidazol-5-yl-carboxylic
acid-N-(3-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-
hydrochloride and n-octyl chloroformate.
Yield: 35 % of theory,
C36H45N7~5 (655.8)
Rf value: 0.28 (silica gel; d_Lchloromethane/ethanol = 19:1)
EKA mass spectrum: (M+H)+ - 656
(M+2H)++ = 328.7
Example 120
1-Methyl-2- [N- [4- (N-n-hexyloxycarbonylamidino) -phenyl] -
N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-
N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-
., amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-
carboxylic acid-N-(2-pyridyl)~-N-(2-ethoxycarbonylethyl)-
amide-hydrochloride and n-hex~~l chloroformate.
Yield: 58 % of theory,
C35H43N7~5 (641.2)
Rf value: 0.42 (silica gel; dichloromethane/ethanol = 19:1)
EKA mass spectrum: (M+H)+ - 642
(M+H+Na)++ = 332.7
- CA 02277949 1999-07-14
- :L22 -
Example 121
1-Methyl-2- [N- [4- (N-n-octylo}ycarbonylamidino) -phenyl] -
N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-
s N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-
amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-
carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-
amide-hydrochloride and n-octyl chloroformate.
Yield: 36 0 of,~theory,
C37H47N7~5 (669.8)
EKA mass spectrum: (M+H)+ - 670
(M+H+Na)++ = 346.8
(M+2H)++ - 335.6
Example 122
1-Methyl-2-[N-[4-(N-n-butyloxycarbonylamidino)-phenyl]-
N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-
N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide
Prepared analogously to Examp:Le 90 from 1-methyl-2-[N-(4-
amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-
carboxylic acid-N-(2-pyridyl)~-N-(2-ethoxycarbonylethyl)-
amide-hydrochloride and n-but~~l chloroformate.
Yield: 34 % of theory,
C33H39N7~5 (613.7)
EKA mass spectrum: (M+H)+ - 614
(M+H+Na)++ = 318.7
(M+Na)+ - 636
CA 02277949 1999-07-14
- 123 -
Example 123
1-Methyl-2- [N- [4- (N-benzoylam:idino) phenyl] -N-methyl-amino-
methyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-
N-(2-ethoxycarbonylethyl)-amide
Prepared analogously to Examp:Le 90 from 1-methyl-2-[N-(4-
amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-
carboxylic acid-N-(2-pyridyl)~-N-(2-ethoxycarbonylethyl)-
amide-hydrochloride and benzo;rl chloride.
Yield: 63 % of theory,
C35H35N704 (617.7)
EKA mass spectrum: (M+H)+ - 618
~,;. ,~,: , ..:.- . ( M+H+Na ) ++ = 3 2 0 . 7
°' . . (M+Na) + - 640
Example 124
1-Methyl-2-[(4-amidinophenyl)c>xymethyl]-benzimidazol-5-yl-
(1-ethoxycarbonylmethyl-cyclohex-1-yl)-ketone-hydrochloride
a) 4-Chloro~henyl-(1-hydroxyca.rbonvlmethyl-cyclohex-1-yl)-
ketone
"~' 8.4 g (40 mMol) of 3-(4-chlorobenzoyl)-propionic acid were
dissolved in 300 ml of tetrahydrofuran and 5.8 g (120 mMol)
of sodium hydride (50-60% suspension in paraffin oil) were
added in batches. Then the mixture was refluxed for 1.5
hours with stirring, after which 8.9 ml (60 mMol) of 1,5-
diiodopentane were added dropwise and boiling was continued
for a further three hours. After cooling the solution was
stirred into 200 ml of ice-water, then the tetrahydrofuran
was distilled off -in vacuo, the resulting aqueous solution
was acidified with 2N hydrochloric acid and extracted three
times with 150 ml of dichloromethane. The organic phase
was dried and evaporated down, the crude product thus
obtained was purified by column chromatography (500 g
silica gel; eluant: dichloromethane with 1-2% ethanol).
....__ _ ......CA.-U2277949 1999-07-14-~___._.___ __...________.....
- 7L24 -
Yield: 6.2 g (55°s of theory) of oily product,
C15H17C103 (280.8)
Rf value: 0.56 (silica gel; dichloromethane/ethanol - 19:1)
b) 4-Chloro-3-nitrophenyl-(1-~hydroxycarbonvlmethyl-
cyclohex-1-yl)-ketone
7.0 g (25 mMol) of 4-chlorophenyl-(1-hydroxycarbonyl-
methylcyclohex-1-yl)-ketone were added in batches, with
stirring, at -5 to -10°C, to 80 ml of fuming nitric acid.
The solution was then stirred for a further 10 minutes,
then stirred into 200 ml of i.ce-water, the precipitated
product was then washed with water and dried.
Yield: 7.8 g (96% of theory),
C15H16C1N05 (325.8)
Rf value: 0.41 (silica gel; petroleum ether/ethyl acetate
4:6)
c) 4-Methylamino-3-nitrophenyl-(1-hydroxycarbonylmethyl-
cyclohex-1-yl)-ketone
7.8 g ( 23.9 mMol) of 4-chloro-3-nitrophenyl-(1-
hydroxycarbonylmethyl-cyclohex-1-yl)-ketone were stirred in
100 ml of a 40% aqueous methylamine solution at room
temperature for 14 hours, then diluted with about 150 ml of
- water and made slightly acidic with glacial acetic acid.
The precipitated product was suction filtered, washed with
water and dried.
Yield: 7.1 g (93% of theory),
C16H20N205 (320.4)
Rf value: 0.34 (silica gel; dichloromethane/ethanol = 19:1)
d) 4-Methylamino-3-nitrophenyl-(1-methoxycarbonylmethyl-
cvclohex-1-yl)-ketone
4.9 g (15 mMol) of 4-methylamino-3-nitrophenyl-(1-
hydroxycarbonylmethyl-cyclohe:x-1-yl)-ketone were dissolved
in 100 ml of tetrahydrofuran, 2.4 g (15 mMol) of 1,1'-
carbonyl-diimidazole were added and the mixture was
refluxed for 15 minutes. Then the solvent was evaporated
CA 02277949 1999-07-14
- 7.25 -
off, 30 ml of methanol were added and the mixture was
boiled for three hours with stirring. After the methanol
had been distilled off the crude product thus obtained was
purified by column chromatography (250 g silica gel,
eluant: dichloromethane with 1 to S% ethanol).
Yield: 2.4 g (48% of theory),
C17H22N2~5 (334.4)
Rf value: 0.76 (silica gel; d:ichloromethane/ethanol = 19:1)
e) 3-Amino-4-methylaminophenyl-(1-methoxycarbonylmethyl-
cyclohex-1-y1) -ketone
2.4 g (7.2 mMol) of 4-methylamino-3-nitrophenyl-(1-
methoxycarbonylmethyl-cyclohe:x-1-yl)-ketone were
catalytically hydrogenated in 100 ml of methanol at room
temperature under 5 bar hydrogen pressure (10% palladium on
charcoal). The crude product thus obtained was further
reacted without purification.
Yield: 2.1 g (96% of theory),
Rf value: 0.34 (silica gel; di.chloromethane/ethanol = 19:1)
f) 3- (4-C'vanophenyloxyacetylarnino) -4-methylaminophenyl-
~1-methoxycarbo ~lmethyl-cyclohex-1-yl)-ketone
620 mg (3.5 mMol) of 4-cyanophenyloxyacetic acid and 570 mg
,~ (3.5 mMol) of 1,1'-carbonyl-diimidazole were refluxed in
50 ml of tetrahydrofuran for 7_5 minutes. Then 1.0 g (3.28
mMol) of 3-amino-4-methylaminophenyl-(1-methoxycarbonylme-
thyl-cyclohex-1-yl)-ketone wex-a added and the mixture was
boiled for a further 4 hours. Then the solvent was
evaporated off and the crude product thus obtained was
purified by column chromatography (150 g silica gel;
eluant: dichloromethane with 0 to 2% ethanol).
Yield: 1.4 g (93% of theory),
C26H29N3~5 (463.5)
Rf value: 0.44 (silica gel; di~~hloromethane/ethanol = 19:1)
. .~CA 02277949 1999-07-14
- 126 -
g) 1-Methyl-2-f(4-cyanophenyT)oxymethyll-benzimidazol-5 y1
(1-methoxycarbonylmethyl-cvc7_ohex-1-yl)-ketone
1.4 g (3.02 mMol) of 3-(4-cyanophenyloxyacetylamino)-4-
methylaminophenyl-(1-methoxyc:arbonylmethyl-cyclohex-1-yl)-
ketone were refluxed in 50 ml. of glacial acetic acid for
one hour. Then the glacial acetic acid was distilled off,
the residue was mixed with 20 ml of water and made alkaline
with concentrated ammonia. 'This solution was extracted
three times with 20 ml of dichloromethane, the organic
extracts were dried and evaporated down. The crude product
thus obtained was purified by column chromatography (100 g
silica gel; eluant: dichlorom.ethane with 0 to 2% ethanol).
Yield: 700 mg (52% of theory),
C26H27N304 (445.5)
h) 1-Methyl-2-f(4-amidinophenyl)oxymethyll-benzimidazol-5-
yl-(1-ethoxycarbonylmethyl-cyclohex-1-yl)-ketone-
hydrochloride
Prepared analogously to Example 25d from 700 mg (1.57 mMol)
of 1-methyl-2-(4-cyanophenylo:xymethyl)-benzimidazol-5-yl-
(1-methoxycarbonylmethyl-cyclohex-1-yl)-ketone with
ethanolic hydrochloric acid and ammonium carbonate.
Yield: 390 mg (50% of theory),
,..-.. C27H32N404 (476.6)
EKA mass spectrum: (M+H) + = 4'77
1H-NMR spectrum(d6-DMSO): 1.:L0 (t,3H); 1.0-2.15 (m,lOH);
3.36 (s,3H); 3.90 (s,2H); 3.94 (q,2H); 5.60 (s,2H);
7.25-7.40 (m,3H); 7.56-7.75 (rn,2H); 7.90 (d,2H); 9.20
(broad s,4H) ppm.
CA 02277949 1999-07-14
- :L27 -
Example 125
1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl)-benzimidazol-
5-yl-tert.butyl-ketone-hydrochloride
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-
cyanophenyl)-aminomethyl]-benzimidazol-5-yl-tert.butyl-
ketone, ethanolic hydrochloric acid, ethanol and ammonium
carbonate.
Yield: 59 % of theory,
C21H25N5~ (363.5)
EKA mass spectrum: (M+H)+ = 364
Example 126
1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-
5-yl-(1-methylcyclopent-1-yl)-ketone-hydrochloride
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-
cyanophenyl)-aminomethyl]-benzimidazol-5-yl-(1-
methylcyclopent-1-yl)-ketone, ethanolic hydrochloric acid,
ethanol and ammonium carbonate.
Yield: 63.5 % of theory,
C23H27N5~ (389.5)
EKA mass spectrum: (M+H)+ = 390
____..... _.______________CA-U2277949 1999-07-14 -__. _ __..__..._.
- 7_28 -
Example 127
2-[(4-amidinophenyl)sulphinyl.methyl]-benzothiazol-5-yl-
carboxylic acid-N-phenyl-N-(2;-ethoxycarbonylethyl)-amide-
hydrochloride
A solution of 0.15 g (0.27 mN~ol) of 2-[(4-
amidinophenyl)thiomethyl]-ben.zothiazol-5-yl-carboxylic
acid-N-phenyl-N-(2-ethoxycarb~onylethyl)-amide-hydrochloride
in 10 ml of acetic acid was mixed with 0. [sic] ml (about
0.81 mMol) of 30o hydrogen peroxide solution and stirred at
'~ room temperature. After 4 days a further 0.18 ml of
hydrogen peroxide solution was added and the resulting
mixture was stirred for a further two days. After removal
of the solvent in vacuo the crude product obtained was
purified by flash chromatography (silica gel; methylene
chloride/ethanol = 10:1 to 4:1).
Yield: 58 % of theory,
C27H26N4~4S2 (534.66)
Rf value: 0.24 (silica gel; methylene chloride/ethanol
- 4:1
+ a few drops of acetic acid)
EKA mass spectrum: (M+H) + = 5:35
Example 128
1-Methyl-2-[(4-amidinophenyl):aulphonylmethyl]-benzimidazol-
5-yl-carboxylic acid-N-(n-propyl)-N-(2-
ethoxycarbonylethyl)-amide-hydrochloride
A solution of 0.40 g (0.70 mMol) of 1-methyl-2- [ (4-
amidinophenyl)thiomethyl]-benzimidazol-5-yl-carboxylic
acid-N-(n-propyl)-N-(2-ethoxycarbonylethyl)-amide-
hydrochloride in 10 ml of forrnic acid was mixed with 2 ml
of 30% hydrogen peroxide solut=ion and the mixture was
stirred for 16 hours at room temperature. Then the solvent
was distilled off in vacuo, whereupon the desired compound
CA 02277949 1999-07-14
- 7L29 -
was obtained as a beige solid (contaminated with some
1-methyl-2-[(4-amidinophenyl)sulfinylmethyl]-benzimidazol-
5-yl-carboxylic acid-N-(n-propyl)-N-(2-
ethoxycarbonylethyl)-amide-hydrochloride).
Yield: 95 % of theory,
C25H31N605S (513.62)
Rf value: 0.50 (silica gel; ethyl acetate/ethanol/1N
hydrochloric acid
- 50:45:5)
EKA mass spectrum: (M+H)+ = 514
Example 129
2- [N- (4-amidinophenyl) -aminomethyl] -thiazolo [5, 4-b] pyridin-
6-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-
amide-hydrochloride
a) Methyl 5-amino-6-chloro-nicotinate
A solution of 1.08 g (5.00 mMol) of methyl 6-chloro-5-
nitro-nicotinate (see A.H. Be:rrie, G.T. Newbold, F.S.
Spring in J. Chem. Soc., 2590, 1951) in [sic] ml of
absolute ethanol was mixed successively with 0.53 ml (29
mMol) of water, 3.2 g (57 mMo:1) of iron powder and 0.030 ml
,,,..,, of concentrated hydrochloric <acid and heated to boiling for
one hour. Then equal quantities of water, iron powder and
hydrochloric acid were added <~nd the mixture was heated to
boiling for 30 minutes. The precipitate formed on cooling
was filtered off and washed with ethanol and the solvent
was distilled off in vacuo.
Yield: 0.75 g (81% of theory) of greenish-yellow solid,
Rf value: 0.31 (silica gel;ethyl acetate/petroleum ether =
1:4)
C7H7C1N202 (186.60)
YEF- Mass spectrum: M+ = 186 and 188 (chlorine isotopes).
. CA 02277949 1999-07-14
- :13 0 -
b) Methyl 6-chloro-5-methoxyacetamido-nicotinate
A solution of 0.75 g (4.02 mPdol) of methyl 5-amino-6-
chloro-nicotinate and 0.43 g = 0.35 ml (4.5 mMol) of
methoxyacetylchloride in 20 rnl of chlorobenzene was stirred
for one hour at 110°C. After the solvent had been removed
in vacuo the crude product obtained was purified by flash
chromatography (silica gel; rnethylene chloride/ethanol =
100:1), evaporated down again in vacuo and then digested
with petroleum, ether.
Yield: 0.55 g '(53% of theory) light yellow amorphous solid,
Rf value: 0.33 (silica gel; ethyl acetate/petroleum ether =
1:4)
c) Methyl 2-methoxymethyl-thiazolof5,4-bhyridin-6-yl-
carboxylate
A mixture of 0.53 g (2.05 mMc>1) of methyl 6-chloro-5-
methoxyacetamido-nicotinate and 0.42 8 (1.0 mMol) of
Lawessons reagent was refluxe~d for 16 hours in 25 ml of
xylene. After the solvent hard been removed in vacuo the
crude product obtained was purified by flash chromatography
(silica gel; methylene chlori.de/ethanol = 100:1) and
evaporated down again in vacuo.
'""~' Yield: 0.33 g (67% of theory) of yellow amorphous solid,
Rf value: 0.52 (silica gel; ethyl acetate/petroleum ether =
1:4)
d) 2-Methox~meth~l-thiazolof5,4-blpyridin-6-yl-carboxylic
acid
A mixture of 1.1 g (4.62 mMol) of methyl 2-methoxymethyl-
thiazolo[5,4-b]pyridine-6-carboxylate and 9.2 ml of 2N
sodium hydroxide solution were stirred into 50 ml of
ethanol for one hour at room temperature. Then 9.2 ml of
2N hydrochloric acid were added, the alcohol was distilled
off, and it was diluted with 20 ml of water. The aqueous
phase was acidified with concentrated hydrochloric acid
CA 02277949 1999-07-14
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whilst cooling with ice, the beige precipitate formed was
filtered off, then washed with water and dried.
Yield: 1.03 g (100% of theory),
Rf value: 0.10 (silica gel; ethyl acetate/petroleum ether =
3:7)
e) 2-Methoxymeth~rl-thiazolof5~4-b]pyridin-6-yl-carboxylic
acid-N-t~henyl-N-(2-ethoxycarbonylethyl)-amide
A suspension of 1.03 g (4.62 mMol) of 2-methoxymethyl-
thiazolo[5,4-b]pyridin-6-yl-carboxylic acid in 40 ml of
methylene chloride was mixed with 1.6 g = 1.0 ml (13.5
''' mMol) of thionyl chloride and refluxed for 90 minutes,
during which time the solid gradually dissolved. After the
liquid components had been distilled off the crude product
was taken up twice more in methylene chloride and
concentrated again. The resulting crude acid chloride
(1.2 g) was taken up in 40 ml of tetrahydrofuran, added
dropwise to a mixture of 0.94 g (4.86 mMol) of N-(2-ethoxy-
carbonylethyl)aniline and 2.1 ml (13.8 mMol) of
triethylamine in 30 ml of tet:rahydrofuran and stirred for 2
hours at room temperature. Tlzen it was diluted with 200 ml
of ethyl acetate, washed with 100 ml of 14% saline solution
and the organic phase was driE:d with sodium sulphate.
After the solvent had been removed in vacuo the crude
product obtained was purified by flash chromatography
(silica gel; methylene chloride/ethanol = 100:1).
Yield: 1.57 g (87% of theory)of yellow oil,
Rf value: 0.55 (silica gel; methylene chloride/ethanol =
19:1)
f) 2-~N- (4-Cyanophenyl) -aminomethylJ -thiazolo f5, 4-bl -
pyridin-6-yl-carboxylic acid-Dl-phenyl-N-(2-
etho~carbonylethyl)-amide
A mixture of 1.54 g (3.85 mMol.) of 2-methoxymethyl-
thiazolo[5,4-b]pyridin-6-yl-ca.rboxylic acid-N-phenyl-N-(2-
ethoxycarbonylethyl)-amide and 4.3 ml (4.3 mMol) of a 1
molar solution of boron tribromide in methylene chloride
CA 02277949 1999-07-14
- 1.32 -
was dissolved in a further 30 ml of methylene chloride and
stirred for 5 hours at room temperature. Then the mixture
was washed with 40 ml of saturated sodium hydrogen
carbonate solution, the organic phase was dried with sodium
sulphate and the solvent was distilled off. The crude
product (1.9 g) was taken up in 15.0 ml of N,N-diisopropyl-
ethylamine, mixed with 0.50 g (4.2 mMol) of
4-aminobenzonitrile and heated to boiling for one hour.
Then the solvent was distilled off in vacuo, the crude
product was taken up in 100 ml of methylene chloride, the
organic phase was washed with 100 ml of water and dried
"'~ with sodium sulphate. After the solvent had been removed
in vacuo the crude product obtained was purified by flash
chromatography (silica gel; ethyl acetate/petroleum ether =
35:65 to 1:1) and evaporated down again in vacuo.
Yield: 0.45 g (24°s of theory) of yellow amorphous solid,
Rf value: 0.34 (silica gel; ethyl acetate/petroleum ether =
1:1)
g) 2-fN-(4-amidinophenyl)-aminomethyl~-thiazolof5,4-bl-
pyridin-6-yl-carboxylic acid-N-phenyl-N-(2-
ethoxycarbonylethyl)-amide-hydrochloride
0 . 3 9 g ( 0 . 8 0 3 mMol ) of 2 - [N- ( 4 - cyanophenyl ) - aminomethyl ] -
thiazolo[5,4-b]pyridin-6-yl-carboxylic acid-N-phenyl-N-(2-
ethoxycarbonylethyl)-amide were stirred in 40 ml of ethanol
saturated with hydrogen chlor~.de for 5 hours first at 0°C
and then at room temperature, until no more starting
material could be detected by thin layer chromatography.
Then the solvent was distilled off at a maximum bath
temperature of 30°C, the oily residue was taken up in 40 ml
of absolute ethanol and mixed with 0.5 g ammonium
carbonate. After 18 hours the' solvent was removed in vacuo
and the crude product obtained was purified by flash
chromatography (silica gel; meahylene chloride/ethanol =
9:1 to 4:1).
Yield: 78 % of theory of yellc>w foam,
CA 02277949 1999-07-14
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C26H26N603S (502.60)
Rf value: 0.19 (silica gel; mesthylene chloride/ethanol
- 4:1
+ a few drops of acetic acid)
EKA mass spectrum: (M+H)+ = 503
Examt~le 130
1-Methyl-2-[(4-amidinophenyl)methylthio]-benzimidazol-5-yl-
carboxylic acid-N-phenyl-N-(2~-ethoxycarbonylethyl)-amide-
hydrochloride
a) 1-Methyl-2-mercapto-benzim:idazol-5-yl-carboxylic acid-N-
phenyl-N-(2-ethoxycarbonyleth~~l)-amide
A solution of 6.5 g (19 mMol) of 3-amino-4-methylamino-
benzoic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide and
4.5 g (22.8 mMol) of N,N~-thiocarbonyldiimidazole were
dissolved in 100 ml of tetrahydrofuran under a nitrogen
atmsphere, the solution was heated to 90°C for 4 hours and
left to stand for 16 hours at room temperature. After
removal of the solvent in vacuo the crude product obtained
was purified by flash chromatography (silica gel; petroleum
ether/ethyl acetate = 100:0 to 65:35).
."-. Yield: 6.8 g (93 % of theory) of beige crystalline solid,
Rf value: 0.55 (silica gel; ethyl acetate)
b) 1-Methyl-2-f(4-cyanophenyl)methvlthio~-benzimidazol-5-
yl-carboxylic acid-N phenyl-N-(2-ethoxycarbonylethyl)-amide
A solution of 1.30 g (3.4 mMol) of 1-methyl-2-mercapto-
benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-
ethoxycarbonylethyl)-amide, 0.52 g (3.74 mMol) of potassium
carbonate and 0.66 g (3.4 mMol) of 4-bromo-
methylbenzonitrile were dissolved in 40 ml of absolute
ethanol, stirred for 4 hours at 60°C and 16 hours at room
temperature. Then the solvent was distilled off in vacuo,
the crude product was taken up in 30 ml of methylene
chloride, washed with 40 ml of water and dried with sodium
CA 02277949 1999-07-14
- 7L34 -
sulphate. After filtration wind distillation of the solvent
the desired compound was obtained as a beige-white solid.
Yield: 1.8 g (100 % of theory),
Rf value: 0.64 (silica gel; ethyl acetate)
c) 1-Methyl-2-f(4-amidinopherwl)methylthiol-benzimidazol-5-
yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-
amide-hydrochloride
1.5 g (3.0 mMol) of 1-methyl-2-[(4-cyanophenyl)methylthio]-
benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-
ethoxycarbonylethyl)-amide were stirred in 80 ml of ethanol
'"'w saturated with hydrogen chloride for 6.5 hours first at
0°C, then at room temperature, until no more starting
material could be detected by thin layer chromatography.
Then the solvent was distilled off at a maximum bath
temperature of 30°C, the oily residue taken up in 80 ml of
absolute ethanol and mixed with 1.0 g (10.5 mMol) of
ammonium carbonate. After 18 hours the solvent was
distilled off in vacuo and the crude product obtained was
purified by flash chromatography (silica gel; methylene
chloride/ethanol = 19:1 to 10:1).
Yield: 78 % of theory of light beige solid,
C28H29N5~3S (515.63)
~~~ Rf value: 0.19 (silica gel; methylene chloride/ethanol =
4:1)
EKA mass spectrum: (M+H)+ - 516
(M+H+Na)++ = 269.7
(M+2H)++ - 258.7
Example 131
1-Methyl-2-[(4-amidinophenyl)methylthio~-benzimidazol-5-yl-
carboxylic acid-N-phenyl-N-(2~-hydroxycarbonylethyl)-amide-
hydrochloride
CA 02277949 1999-07-14
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Prepared analogously to Example 10 from 1-methyl-2-[(4-
amidinophenyl)methylthio]-benzimidazol-5-yl-carboxylic
acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride
and sodium hydroxide solution.
Yield: 57 % of theory,
C26H25N5~3S (487.58)
Rf value: 0.23 (Reversed Phase silica gel RP-8; Methanol/5o
saline solution = 6:4)
EKA mass spectrum: (M+H)+ - 488
( M+Na ) + - 510
"~ ( M+Na+H ) ++ = 2 5 5 . 6
Example 132
1-Methyl-2-[N-(4-amidinopheny7!)-aminomethyl]-benzimidazol-
5-yl-carboxylic acid-N-proparc~yl-N-(2-ethoxycarbonylethyl)-
amide-hydrochloride
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-
cyanophenyl)-aminomethyl]-ben~:imidazol-5-yl-carboxylic
acid-N-propargyl-N-(2-ethoxycarbonylethyl)-amide, ethanolic
hydrochloric acid, ethanol and ammonium carbonate.
Yield: 81 % of theory,
C25H28N6~3 (460.6)
Rf value: 0.094 (silica gel; dichloromethane/ethanol = 4:1)
EKA mass spectrum: (M+H)+ - 461
(M+H+Na) ++ = 242
(M+2H)++ - 231
Example 133
1-Methyl-2- [2- [4- (N-n-
hexyloxycarbonylamidino)phenyl]ethyl]-benzimidazol-5-yl-
carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-
amide
CA 02277949 1999-07-14
- 136 -
Prepared analogously to Example 90 from 1-methyl-2-[2-(4-
amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-
(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride
and n-hexyl chloroformate.
Yield: 72 0 of theory,
C35H42N6~5 (626.8)
Rf value: 0.54 (silica gel; dichloromethane/methanol = 9:1)
EKA mass spectrum: (M+H) + - 627
( M+Na ) + _ ~5 4 9
Example 134 '
1-Methyl-2- [2- [4- (N-benzoylam:idino) phenyl] ethyl] -
benzimidazol-5-yl-carboxylic <~cid-N-(2-pyridyl)-N-(2-
ethoxycarbonylethyl)-amide
Prepared analogously to Example 90 from 1-methyl-2-[2-(4
amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N
(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride
and benzoyl chloride.
Yield: 79 % of theory,
C35H34N6~4 (602.7)
Rf value: 0.52 (silica gel; dichloromethane/methanol = 9:1)
EKA mass spectrum: (M+H) + - E>03
2 5 ( M+Na ) + = E. 2 5
Example 135
1-Methyl-2- [2- [4- (N-nicotinoylamidino) phenyl] ethyl] -
benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-
ethoxycarbonylethyl)-amide
Prepared analogously to Example 90 from 1-methyl-2-[2-(4-
amidinophenyl)ethyl]-benzimida.zol-5-yl-carboxylic acid-N-
(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride
and nicotinic acid chloride.
CA 02277949 1999-07-14
- 137 -
Yield: 56 % of theory,
C34H33N7~4 (603.7)
Rf value: 0.52 (silica gel; dichloromethane/methanol - 9:1)
EKA mass spectrum: (M+H)+ - 604
(M+Na) + = 626
Example 136
1-Cyclopropyl-2-[N-(4-amidinophenyl)-aminomethyl]-
benzimidazol-5-yl-carboxylic .acid-N-phenyl-N-(2-
ethoxycarbonylethyl)-amide-hydrochloride
Prepared analogously to Example 25d from 1-Cyclopropyl-2-
[N-(4-cyanophenyl)-aminomethy:l]-benzimidazol-5-yl-
carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide,
ethanolic hydrochloric acid, ethanol and ammonium
carbonate.
Yield: 31 % of theory,
C3pH33N6~3 (524.6)
Rf value: 0.40 (silica gel; dichloromethane/methanol = 5:1)
EKA mass spectrum: (M+H)+ - 525
(M+H+Na)++ = 274
(M+2H)++ - 263
Example 137
1-Cyclopropyl-2- [N- (4-amidinophenyl) -aminomethyl] -
benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-
hydroxycarbonylethyl)-amide
Prepared analogously to Example 26 from 1-cyclopropyl-2-(N
(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic
acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride
and sodium hydroxide solution.
Yield: 64 % of theory,
CA 02277949 1999-07-14
- 138 -
C28H28N6~3 (496.6)
EKA mass spectrum: (M+H)+ - 497
(M+H+Na)++ = 260
(M+Na)+ - 519
(M+2Na) ++ - 271
,r
CA 02277949 1999-07-14
- 139 -
Example 138
1-Methyl-2-[N-(4-amidinopheny:l)-N-(n-butyl)-aminomethyl]-
benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-
ethoxycarbonylethyl)-amide-hydrochloride
Prepared analogously to Examp:Le 25d from 1-methyl-2-[N-(4-
cyanophenyl)-N-(n-butyl)-aminomethyl]-benzimidazol-5-yl-
carboxylic acid-N-phenyl-N-(2~-ethoxycarbonylethyl)-amide,
ethanolic hydrochloric acid, Eahanol and ammonium
carbonate.
.~-~ Yield: 62 % of theory,
C32H38N6~3 (554.7)
EKA mass spectrum: (M+H)+ - 555
( M+H+Na ) ++ = 2 8 9
(M+2H)++ - 278
Example 139
1-Methyl-2-[N-(4-amidino-2-chl_oro-phenyl)-aminomethyl]-
benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-
ethoxycarbonylethyl)-amide-hydrochloride
-°'°~ Prepared analogously to Example 25d from 1-methyl-2-[N-(4-
cyano-2-chloro-phenyl)-aminomeahyl]-benzimidazol-5-yl-
carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide,
ethanolic hydrochloric acid, eahanol and ammonium
carbonate.
Yield: 82 % of theory,
C28H2gC1N603 (533.1)
EKA mass spectrum: (M+H)+ - 533/5
(M+H+Na)++ = 278/9
CA 02277949 1999-07-14
- :L40 -
Example 140
1-Methyl-2- [N- [4- (n-octyloxyc:arbonylamidino) phenyl] -
aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-
(2-ethoxycarbonylethyl)-amide'
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-
amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic
acid-N-phenyl-N-(2-ethoxycarx>onylethyl)-amide-hydrochloride
and n-octyl chloroformate.
Yield: 34 % of,'theory,
'"~' C37H46N6C5 (654.8)
Rf value: 0.15 (silica gel; d:ichloromethane/ethanol = 19:1)
EKA mass spectrum: (M+H)+ - 655
( M+H+Na ) ++ = 3 3 9
(M+Na)+ - 677
Example 141
1-Methyl-2-[N-(4-amidino-2-ethyl-phenyl)-aminomethyl]-
benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-
ethoxycarbonylethyl)-amide-hydrochloride
°~ Prepared analogously to Example 25d from 1-methyl-2-[N-(4-
cyano-2-ethyl-phenyl)-aminomethyl]-benzimidazol-5-yl-
carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide,
ethanolic hydrochloric acid, ethanol and ammonium
carbonate.
Yield: 61 % of theory
C3pH34N6~3 (526.6)
EKA mass spectrum: (M+H)+ - 527
(M+H+Na) ++ = 275
(M+2H) ++ - 264
CA 02277949 1999-07-14
- 141 -
Example 142
1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-
5-yl-carboxylic acid-benzylam.ide-hydrochloride
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-
cyanophenyl)-aminomethyl]-ben;aimidazol-5-yl-carboxylic
acid-benzylamide, ethanolic hydrochloric acid, ethanol and
ammonium carbonate.
Yield: 63 % of theory,
C24H24N6~ (412.5)
~''-' Rf value: 0.76 (silica gel; dichloromethane/ethanol = 4:1)
EKA mass spectrum: (M+H) + = 4:L3
Example 143
1-Methyl-2- [N- [4- (N- (2- (2-ethoxyethoxy) ethyloxy) -
carbonylamidino)-phenyl)-aminomethyl]-benzimidazol-5-yl-
carboxylic acid-N-(2-pyridyl)-~N-(2-ethoxycarbonylethyl)-
amide
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-
amidinophenyl)-aminomethyl]-be~nzimidazol-5-yl-carboxylic
acid-N-(2-pyridyl)-N-(2-ethoxy~carbonylethyl)-amide-
hydrochloride and diethyleneglycolmonoethylether
chloroformate.
Yield: 43 % of theory,
C34H41N7~7 (659.8)
Rf value: 0.56 (silica gel; dichloromethane/methanol = 9:1)
EKA mass spectrum: (M+H)+ = 660
(M+H+Na)++ = 341.7
CA 02277949 1999-07-14
- :L42 -
Example 144
1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-
5-yl-carboxylic acid-N-(1-met:hylpyrazol-4-yl)-N-(2-
ethoxycarbonylethyl)-amide-hydrochloride
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-
cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic
acid-N- (2-pyridyl) -N- (2-etho~sycarbonylethyl) -amide,
ethanolic hydrochloric acid, ethanol and ammonium
carbonate.
--, Yield: 60 % of theory,
C26H30N8~3 (502.6)
Rf value: 0.13 (silica gel; d.ichloromethane/ethanol = 4:1)
EKA mass spectrum: (M+H)+ - 503
(M+H+Na)++ = 263
(M+2H)++ - 252
Example 145
3-Methyl-2-[(4-amidinophenyl)-thiomethyl]-imidazo[4,5-b]-
pyridin-6-yl-carboxylic acid-N-phenyl-N-(2-
ethoxycarbonylethyl)-amide-hydrochloride
Prepared analogously to Example 1 from 3-methyl-2-[(4-
cyanophenyl)thiomethyl]-imidazo[4,5-b]pyridin-6-yl-
carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide,
ethanolic hydrochloric acid, ethanol and ammonium
carbonate.
Yield: 88 % of theory,
C27H28N603S (516.63)
Rf value: 0.23 (silica gel; ethyl acetate/ethanol/ammonia =
50:45:5)
EKA mass spectrum: (M+H)+ - 517
3 5 ( M+H+Na ) ++ = 2 7 0
CA 02277949 1999-07-14
- 1.43 -
Example 146
3-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-
imidazo[4,5-b]pyridin-6-yl-carboxylic acid-N-phenyl-N-
(2-ethoxycarbonylethyl)-amide-hydrochloride
Prepared analogously to Example 1 from 3-methyl-2-[N-(4-
cyanophenyl)-aminomethyl]-imidazo[4,5-b]pyridin-6-y1-
carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide,
ethanolic hydrochloric acid, ethanol and ammonium
carbonate.
Yield: 82 % of theory,
C27H29N7~3 (499.58)
Rf value: 0.20 (silica gel; ethyl acetate/ethanol/ammonia =
50:45:5)
EKA mass spectrum: (M+H)+ - 500
(M+H+Na)++ = 261.7
Example 147
3-Methyl-2-[(4-amidinophenyl)--thiomethyl]-
imidazo[4,5-b]pyridin-6-yl-carboxylic acid-N-phenyl-N-
,,.-. ( 2 -hydroxycarbonylethyl ) -amide.-hydrochloride
Prepared analogously to Examp7_e 2 from 3-methyl-2-[(4-
amidinophenyl)-thiomethyl]-imidazo[4,5-b]pyridin-6-yl-
carboxylic acid-N-phenyl-N-(2--ethoxycarbonylethyl)-amide-
hydrochloride and sodium hydroxide solution.
Yield: 88 % of theory,
C25H24N603S (488.56)
Rf value: 0.21 (silica gel; ethyl acetate/ethanol/ammonia =
50:45:5)
EKA mass spectrum: (M+H)+ - 489
3 5 ( M+Na ) + = 511
CA 02277949 1999-07-14
- 1.44 -
Example 148
3-Methyl-2-[N-(4-amidinophenyl)-aminomethyl)-
imidazo[4,5-b)pyridin-6-yl-carboxylic acid-N-phenyl-N-
(2-hydroxycarbonylethyl)-amide-hydrochloride
Prepared analogously to Example 2 from 3-methyl-2-[N-(4-
amidinophenyl) -aminomethyl] -imidazo [4, 5-b) pyridin-6-yl-
carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-
hydrochloride and sodium hydroxide solution.
Yield: 80 0 of theory,
C25H25N7~3 (471.52)
Rf value: 0.19 (silica gel; ethyl acetate/ethanol/ammonia =
50:45:5)
EKA mass spectrum: (M+H) + -- 472
( M+Na ) + -- 4 9 4
(M+2Na) ++ _- 258 . 6
Example 149
1-Methyl-2-[N-(4-amidinophenyl_)-aminomethyl)-benzimidazol-
.~ 5-yl-sulphonic acid-N-phenyl-Dl-(2-ethoxycarbonylethyl)-
amide-hydrochloride
a) 1-Methyl-2fN-(4-cyanophenyl.)-aminomethvll-benzimidazol-
5-yl-sulphonic acid-N phenyl-N-(2-ethoxycarbonylethyl)-
amide
2.54 g (6,2 mMol) of 3-nitro-4-methylamino-benzenesulphonic
acid-N-phenyl-N-(2-ethoxycarbo~nylethyl)-amide were
hydrogenated at room temperature under 5 bar hydrogen
pressure over palladium/charcoal (10%) in a mixture of
75 ml of ethanol and 75 ml of dichloromethane. The
resulting crude 3-amino-4-methylamino-benzenesulphonic
acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide was taken up
in 30 ml of phospharus oxychloride, without purification,
CA 02277949 1999-07-14
- 145 -
then 1.1 g (6,2 mMol) of N-(4-cyanophenyl)-glycine were
added and the mixture was refluxed for two hours. After
cooling to room temperature the reaction mixture was added
to about 70 ml of water with cooling and in this way the
excess phosphorus oxychloride was destroyed. The resulting
solution was neutralised with solid sodium carbonate and
extracted three times with 30 ml of ethyl acetate. After
evaporation of the solvent th~~ crude product was purified
by column chromatography (100 g silica gel; eluant:
cyclohexane/ethyl acetate = 2:3).
Yield: 860 mg (26.8 % of theo:ry),
Melting point: 188-191°C
C27H27N5~3S (517.6)
Rf value: 0.52 (silica gel; dichloromethane/methanol = 9:1)
EKA mass spectrum: (M+H)+ - 518
( M+Na ) + = 5 4 0
b) 1-Methvl-2- [N- (4-amidinophe:nvl) -aminomethvl
benzimidazol-5-yl-sulphonic acid-N-phenyl-N-
(2-ethoxycarbonvlethyl) -amide--hydrochloride
Prepared analogously to Examp7_e 25d from 1-methyl-2-[N-(4-
cyanophenyl)-aminomethyl]-ben~:imidazol-5-yl-sulphonic acid-
N-phenyl-N-(2-ethoxycarbonylet:hyl)-amide, ethanolic
,.... hydrochloric acid, ethanol and ammonium carbonate.
Yield: 87 % of theory,
C27H30N6~4S (534.6)
Rf value: 0.13 (silica gel; di~~hloromethane/ethanol = 9:1)
EKA mass spectrum: (M+H)+ - 535
( M+H+Na ) ++ = 2 7 9
Example 150
1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-
5-yl-sulphonic acid-N-(1-methylpyrazol-4-yl)-
N-(2-ethoxycarbonylethyl)-amide-hydrochloride
CA 02277949 1999-07-14
- 146 -
Prepared analogously to Example 25d from 1-methyl-2-(N-(4-
cyanophenyl)-aminomethyl]-be:nzimidazol-5-yl-sulphonic acid-
N-(1-methylpyrazol-4-yl)-N-(:2-ethoxycarbonylethyl)-amide,
ethanolic hydrochloric acid, ethanol and ammonium
carbonate.
Yield: 38 0 of theory,
C25H30N8~4S (538.6)
Rf value: 0.09 (silica gel; d.ichloromethane/ethanol - 9:1)
EKA mass spectrum: (M+H) + = 539
Example 151
1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -
5-(2.3-dihydroindol-1-yl-sulphonyl)-benzimidazole-
hydrochloride
Prepared analogously to Example 25d from 1-methyl-2-[N-
(4-cyanophenyl)-aminomethyl]-5-(2.3-dihydroindol-1-yl-
sulphonyl)-benzimidazole and ethanolic hydrochloric acid,
ethanol and ammonium carbonate.
Yield: 15 % of theory,
Rf value: 0.36 (silica gel; dichloromethane/methanol = 4:1)
C24H24N6~2S (460.6)
r
EKA mass spectrum: (M+H)+ = 461
CA 02277949 1999-07-14
- :14 7 -
Example 152
1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazole-
5-yl-sulphonic acid-N-phenyl--N-(2-hydroxycarbonylethyl)-
amide
Prepared analogously to Example 26 from 1-methyl-
2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-
sulphonic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-
hydrochloride and sodium hydroxide solution.
Yield: 24 % of theory,
.-. Rf value: 0.55 (Reverse-Phase: RP-18 silica gel; methanol/5%
saline solution = 3:2)
C25H26N6~4S (506.6)
EKA mass spectrum: (M+H)+ - 507
(M+Na) + - 529
(M+2Na) ++ = 276
Example 153
1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-5-(isoindolin-
2-yl-sulphonyl)-benzimidazol-:hydrochloride
..-
Prepared analogously to Example 25d from 1-methyl-
2- [N- (4-cyanophenyl) -aminometlhyl] -5- (isoindolin-2-yl-
sulphonyl)-benzimidazole and ethanolic hydrochloric acid,
ethanol and ammonium carbonate.
Yield: 33 % of theory,
Rf value: 0.32 (silica gel; dichloromethane/methanol = 4:1)
C24H24N6~2S (460.6)
EKA mass spectrum: (M+H) + = 4E>1
CA 02277949 1999-07-14
- 1.48 -
Example 154
2-[2-(4-Amidinophenyl)-ethyl]-quinazolin-7-yl-carboxylic
acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride
a. Ethyl 4-methyl-3-nitro-benzoate
To a solution of 3 ml of concentrated hydrochloric acid and
4 ml of concentrated sulphuric acid, 4.9 g (0.03 mol) of
ethyl p-tolylate were added dropwise with stirring at 5°C
and stirred for 1 hour whilst cooling in an ice-bath. After
heating to ambient temperature the mixture was poured onto
ice-water and extracted with ethyl acetate. The organic
extracts were washed with sodium hydrogen carbonate
solution, dried and evaporated down.
Yield: 5.7 g (90 % of theory),
Rf value: 0.81 (silica gel, ethyl acetate/cyclohexane =
1:1)
b. Methyl 4-(2-dimethylaminov:inyl)-3-nitro-benzoate
1.0 g (4.8 mmol) of ethyl 4-methyl-3-nitro-benzoate, 0.74 g
(6.2 mmol) of dimethylformam:ide dimethylacetal and 2 ml of
dimethylformamide were heated to 140°C with stirring for 3
hours. Then the solvent was d_Lstilled off and the crude
product thus obtained was reacted without any further
'""~ 25 purification.
Yield: 1.2 g (100 % of theory),
Rf value: 0.54 (silica gel, ethyl acetate/cyclohexane =
1:1)
c. Methyl 4-formyl-3-nitro-benzoate
1.2 g (4.8 mmol) of methyl 4-(2-dimethylaminovinyl)-3-
nitro-benzoate were dissolved in 120 ml of
tetrahydrofuran/water (1:1) and after the addition of 3.0 g
(14.3 mmol) of sodium metaperiodate the mixture was
stirred for 20 hours at ambier.~t temperature. The suspension
was then diluted with water anal methylene chloride and
extracted with methylene chloride. The combined organic
CA 02277949 1999-07-14
- 149 -
extracts were washed with sodium hydrogen carbonate
solution, dried and evaporated down. The residue was
chromatographed on silica gel and eluted with ethyl
acetate/cyclohexane (1:3).
Yield: 0.6 g (63 % of theory),
Rf value: 0.63 (silica gel, ethyl acetate/cyclohexane =
1:1)
d. Methyl 3-Amino-4-formyl-benzoate
To a solution of 25 ml of ethanol/glacial acetic acid/water
(2:2:1) were added 0.6 g (2.9 mmol) of methyl 4-formyl-3-
,,.... nitro-benzoate, 1.2 g (21.4 mmol) of iron powder and
0.01 ml of concentrated hydrochloric acid and the mixture
was refluxed with stirring fo:r 15 minutes. Then the iron
was separated off, the solution was diluted with water and
extracted with methylene chloride. The combined organic
extracts were washed with watE_r, dried and evaporated down.
Yield: 0.3 g (58 % of theory) ,,
Rf value: 0.74 (silica gel, me~thylene chloride/methanol =
9.5:0.5)
e. Methyl 3-[3-(4-cyanophenyl)-propionylamino]-4-formyl-
benzoate
1.0 g (5.6 mmol) of methyl 3-amino-4-formyl-benzoate and
1.1 g (5.6 mmol) of 4-cyanophenylpropionic acid chloride
were dissolved in 50 ml of met:hylene chloride and after the
addition of 0.7 g (5.6 mmol) of N-ethyl-diisopropylamine
the mixture was stirred for 29: hours at ambient
temperature. Then it was extracted with sodium hydrogen
carbonate solution, the combined organic extracts were
dried and evaporated down. The: residue was chromatographed
on silica gel and eluted with ethyl acetate/cyclohexane
(1:3) .
Yield: 0.6 g (32 % of theory),
Rf value: 0.60 (silica gel, ethyl acetate/cyclohexane =
1:1)
CA 02277949 1999-07-14
- 7_50 -
f . Methyl 2- [2- (4-cyanophenyl.) -ethyl] -quinazoline-7-
carboxylate
0.6 g (1.8 mmol) of ethyl 3-[3-(4-cyanophenyl)-
propionylamino]-4-formyl-benzoate and 10 ml of methanolic
ammonia solution were agitated in a pressure vessel for 36
hours. Then the solvent was distilled off, the residue was
chromatographed on silica gel and eluted with methylene
chloride containing 0 to 1 % methanol.
Yield: 0.35 g (62 % of theory),
Rf value: 0.38~(silica gel, ethyl acetate/cyclohexane =
.-
1:1)
g. 2-f2-(4-Cyanophenyl)-ethyl]-auinazolin-7-carboxylic acid
0.3 g (0.94 mmol) of methyl 2- [2- (4-cyanophenyl) -ethyl] -
quinazoline-7-carboxylate were dissolved in 4.7 ml of 1N
lithium hydroxide solution and 4 ml of tetrahydrofuran and
stirred for 3 hours at ambient temperature. Then 4.7 ml of
1N hydrochloric acid were added and the mixture was stirred
for 30 minutes. The product precipitated was suction
filtered, washed with water a:nd dried.
Yield: 0.30 g (100 % of theor;y),
Rf value: 0.1 (silica gel, ethyl acetate/cyclohexane = 1:1)
h. 2-[2-(4-Cyanophenyl)-ethyl:)-quinazolin-7-yl-carboxylic
acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide
0.4 g (1.3 mmol) of 2- [2- (4-cyanophenyl) -ethyl] -
quinazoline-7-carboxylic acid and 5 ml of thionyl chloride
were stirred for 60 minutes a1= 50°C. Then the thionyl
chloride was distilled off, the residue was dissolved in
methylene chloride, mixed with 0.24 g (1.3 mmol) of methyl
3-(N-phenylamino)-propionate and 0.22 ml of (1.3 mmol) of
N-ethyldiisopropylamine and stirred for 18 hours at ambient
temperature. After evaporation of the solvent in vacuo the
CA 02277949 1999-07-14
- 151 -
residue was chromatographed o~n silica gel and eluted with
methylene chloride containing 1 % methanol.
Yield: 230 mg (37 % of theory),
Rf value: 0.64 (silica gel, methylene chloride/methanol -
9:1)
i. 2-[2-(4-Amidinophenyl)-ethyl]-quinazolin-7-yl-carboxylic
acid-N-phenyl-N-(2-ethoxycarbonylethvl)-amide-hydrochloride
230 mg (0.5 mmol) of 2-[2-(4-cyanophenyl)-ethyl]-
quinazolin-7-yl-carboxylic acid-N-phenyl-
N-(2-methoxycarbonylethyl)-amide were stirred in 30 ml of
saturated ethanolic hydrochloric acid for 8 hours at
ambient temperature. Then the mixture was evaporated to
dryness in vacuo, the residue was taken up in 20 ml of
ethanol, combined with 0.5 g (5.0 mmol) of ammonium
carbonate and stirred overnight at ambient temperature.
After evaporation of the solvent the crude product was
chromatographed on silica gel and eluted with methylene
chloride/ethanol (4:1).
Yield: 100 mg (39 % of theory;.,
Rf value: 0.5 (silica gel, met:hylene chloride/ethanol =
4:1)
C29H29N503 (495.59)
Mass spectrum: (M+H)+ = 496
Example 155
1-Methyl-2-[N-(4-amidinophenyl.)-aminomethyl]-benzimidazol-
5-yl-sulphonic acid-N-(1-methylpyrazol-4-yl)-N-(2-
hydroxycarbonylethyl)-amide
Prepared analogously to Example 26 from 1-methyl-2-[N-(4-
amidinophenyl)-aminomethyl]-be:nzimidazol-5-yl-sulphonic
acid-N-(1-methylpyrazol-4-yl)-N-(2-ethoxycarbonylethyl)-
amide-hydrochloride and sodium, hydroxide solution.
CA 02277949 1999-07-14
' - 152 -
Yield: 95 % of theory,
C23H26N804S (510.6)
Rf value: 0.53 (Reversed Phase silica gel RP-18, methanol +
5% saline solution)
EKA mass spectrum: (M+H) + .- 511
(M+Na)+ - 533
(M+2Na) ++ = 278
Example 156
1-Methyl-2-[N-(3-amidino-pyridin-6-yl)-aminomethyl]-
benzimidazol-5-yl-carboxylic <~cid-N-(2-pyridyl)-
N-(2-ethoxycarbonylethyl)-amide-hydrochloride
a) 3-[(N-tert.Butoxycarbonyl-amino)acetylamino]-
4-methylamino-benzoic acid-N-(2-pyridyl)-
N-(2-ethoxycarbonylethyl)-amide
19.2 g (0.11 mol) of N-tert.butyloxycarbonylglycine were
dissolved in 175 ml of dimethylformamide, mixed with 35.2 g
(0.11 mol) of O-benzotriazol-~1-yl)-N,N,N',N'-
tetramethyluronium tetrafluoroborate, 11.0 g of
..- triethylamine and 34.2 g (0.10 mol) of 3-amino-4-methyl-
amino-benzoic acid-N-(2-pyrid~~1)-N-(2-ethoxycarbonylethyl)-
amide and stirred for 2.5 hours at ambient temperature.
Then the reaction solution was. mixed with 5 1 of ice water
and stirred for 2 hours. The grey precipitate formed was
filtered off, washed with water, dried and recrystallised
from ethyl acetate with the addition of activated charcoal.
Yield: 39.85 g (80 % of theory),
C25H33N506 (499.6)
Rf value: 0.55 (silica gel; meahylene chloride/ethanol =
19:1)
CA 02277949 1999-07-14
- 7.53 -
b) 1-Methyl-2-(N-tert.butoxvc:arbonyl-aminomethyl)-
benzimidazol-5-yl-carboxylic acid-N-!2-pyridyl)-
N-(2-ethoxycarbonylethyl)-amide
10.0 g (0.02 mol) of 3-[(N-tert.butoxycarbonyl-
amino)acetylamino]-4-methylamino-benzoic acid-
N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide were
dissolved in 50 ml of glacial acetic acid and refluxed for
one hour. Then the solvent was distilled off, the residue
was mixed with ice water and adjusted to pH 8 by the
addition of 2N ammonia. After extraction three times with
ethyl acetate the combined organic phases were washed with
saline solution and dried over sodium sulphate. After
evaporation of the solvent the crude product was
chromatographed on silica gel, eluting first with methylene
chloride, then with methylene chloride/ethanol (50:1) and
(25:1). The desired fractions were combined and evaporated
down.
Yield: 5.85 g (61 % of theory),
C25H31N5~5 (481.6)
Rf value: 0.70 (silica gel; methylene chloride/ethanol =
9:1)
c) 1-Methyl-2-aminomethyl-benzimidazol-5-vl-carboxylic
acid-N-(2-,gyridyl)-N-(2-ethoxycarbonylethyl)-amide-
trifluoracetate
4.81 g (0.10 mol) of 1-methy:l-2-(N-tert.butoxycarbonyl-
aminomethyl)-benzimidazol-5-y:1-carboxylic acid-
N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide were
dissolved in 25 ml of methylene chloride, mixed with 5 ml
of trifluoroacetic acid and sl.irred for 5 hours at ambient
temperature. Then the solvent was evaporated off and the
residue was stirred with ether. The crystals thus formed
were filtered off, washed with ether and dried.
Yield: 3.15 g (68 % of theory),
C2pH23N5~3 (381.4)
Rf value: 0.18 (silica gel; me~thylene chloride/ethanol =
9:1)
CA 02277949 1999-07-14
- 1.54 -
d) 1-Methyl-2- fN- (3-cyano-pyridin-6-yl) -aminomethyll -
benzimidazol-5 girl-carboxylic acid-N-(2-pvridyl)-
N-(2-ethoxycarbonylethyl)-amide
1.5 g (3.25 mmol) of 1-methyl-2-aminomethyl-benzimidazol-
5-yl-carboxylic acid-N-(2-pyridyl)-
N-(2-ethoxycarbonylethyl)-amide-trifluoracetate were
stirred into 10 ml of N-ethyl-diisopropylamine and heated
to 100°C for 15 minutes. After the addition of 720 mg
(5.25 mmol) of 2-chloro-5-cyano-pyridine the reaction
mixture was heated to 125°C for 2 hours. After cooling to
ambient temperature and stirring with about 20 ml of water,
the pH was adjusted to 4 by t:he addition of 1N hydrochloric
acid and the mixture was extracted 3 times with ethyl
acetate. The combined organic phases were washed with
saline solution and dried over sodium sulphate. After
evaporation of the solvent the crude product was
chromatographed on silica gel, eluting first with methylene
chloride, later with methylenf~ chloride/ethanol (25:1) and
(19:1). The desired fractions were combined and evaporated
down.
Yield: 1.05 g (67 % of theory),
C26H25N70 (483.6)
Mass spectrum: (M+H)+ = 484
e) 1-Methyl-2-fN-(3-amidino-pyridin-6-yl)-aminomethyll-
benzimidazol-5-vl-carboxylic acid-N-(2-rwridvl)-
N-(2-ethoxycarbonylethyl)-amide-hydrochloride
Prepared analogously to Example 25d from 1-Methyl-2-[N-(3-
cyano-pyridin-6-yl)-aminomethyl]-benzimidazol-5-yl-
carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-
amide and ethanolic hydrochloric acid, ethanol and ammonium
carbonate.
Yield: 38 % of theory,
C2gH28N803 (500.6)
CA 02277949 1999-07-14
- 7_55 -
Mass spectrum: (M+H)+ = 501
Example 157
1-Methyl-2-[N-(4-amidinophenyl)aminomethyl]-indol-5-yl-
carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide-
hydroiodide
a) 4-Nitro-benzoic acid-N-phenyl-N-(2-
methoxycarbonylethyl)amide
16.7 g (0.1 moh) of 4-nitrobenzoic acid were refluxed in
,"r", 50 ml of thionyl chloride and 3 drops of dimethylformamide
for 1 hour. After the solvent had been distilled off in
vacuo the crude product was dissolved in 150 ml of
tetrahydrofuran and added dropwise to a solution of 18 g
(0.1 mol) of N-(2-methoxycarbonylethyl)aniline in 250 ml
of tetrahydrofuran and 42 ml 0.3 mol) of triethylamine.
After being stirred for one hour at ambient temperature the
reaction mixture was diluted 'with 250 ml of ethyl acetate
and washed 2x with 200 ml of 14% saline solution. After the
solvent had been distilled off and the residue
chromatographed (silica gel; methylene chloride) a yellow
oil was obtained which slowly solidified.
Yield: 32.6 g (100 0 of theor;y),
Rf value: 0.37 (silica gel; m~~thylene chloride/methanol =
50:1)
b) 4-Amino-benzoic acid-N-phenyl-N-(2-
methoxycarbonylethyl)amide
22 g (67 mmol) of 4-nitro-benzoic acid-N-phenyl-N-(2-
methoxycarbonylethyl)-amide were hydrogenated in 500 ml of
methanol with 2 g of 10% palladium on charcoal at 3 bar
hydrogen pressure for 3 hours. After filtration and
distillation of the solvent the reaction mixture was washed
with 100 ml of ether and the white crystalline product was
further reacted directly.
CA 02277949 1999-07-14
- 7_56 -
Yield: 18.6 g (94 % of theory),
Rf value: 0.70 (silica gel; methylene chloride/ethanol -
19:1)
c) 2-Methyl-3-thiomethyl-indc~1-5-yl-carboxylic acid-N-
phenyl-N-(2-methoxycarbonvlet.hyl)-amide
26.8 g (91 mmol) of 4-amino-benzoic acid-N-phenyl-N-(2-
methoxycarbonylethyl)amide were dissolved in 500 ml of
methylene chloride, cooled to -70°C and mixed within 30
minutes with freshly prepared. tert.butylhypochlorite (M. J.
Mintz et al., Organic Synthesis, Coll. Vol. 5, page 184).
"~ The mixture was stirred for 2 hours at -70°C, then 9.46 g
(91 mmol) of methylthioacetone in 40 ml of methylene
chloride were added dropwise within 10 minutes and stirring
was continued for a further 1.5 hours. Then 12.7 ml (9.1 g,
91 mmol) of triethylamine in 25 ml of methylene chloride
were added. The mixture was left for 30 minutes at -78°C
and then slowly warmed to ambient temperature overnight.
After washing twice with 50 ml of water the organic phase
was separated off and dried with sodium sulphate. After
removal of the solvent in vacuo a white amorphous substance
is obtained after purification by chromatography (silica
gel; ethyl acetate/petroleum .ether = 2:8 to 3:7).
Yield: 24.1 g (69 % of theory),
''~ 25 Rf value: 0.58 (silica gel; ethyl acetate/petroleum ether =
1:1)
C21H22N203S (382.49)
Mass spectrum: (M)+ = 382
CA 02277949 1999-07-14
- :157 -
d) 1-tert-Butoxycarbonvl-2-methyl-indol-5 girl-carboxylic
acid-N-phenyl-N- (2-methoxycarbonylethyl) -amide
8.9 g (23 mmol) of 2-Methyl--3-thiomethyl-indol-5-yl-
carboxylic acid-N-phenyl-N-(a?-methoxycarbonylethyl)-amide
were dissolved in 600 ml of ethanol, mixed with about
150 mg of Raney nickel and stirred for 2 hours at ambient
temperature (analogously to F>.G. Gassman et al., Organic
Synthesis Coll. Vol. 6, page 601). Then the mixture was
filtered and the solvent eliminated in vacuo. The crude
product thus obtained (8 g) was dissolved in 200 ml of
absolute tetrahydrofuran, mixed with 150 mg of
,,... dimethylaminopyridine and 6.84 g (32 mmol) of di-tert.butyl
pyrocarbonate and stirred for 2.5 hours at 50°C. Then the
solvent was distilled off in vacuo and the crude product
was purified by chromatography (silica gel, ethyl
acetate/petroleum ether = 1:4).
Yield: 10.0 g (98 % of theory),
Rf value: 0.40 (silica gel; ethyl acetate/petroleum ether
=3:7)
e) 2fN- (4-Cyanophenyl) aminomethyl~ -indol-5-yl-carboxylic
acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide
3.5 g (8 mmol) of 1-tert.butoxycarbonyl-2-methyl-indol-5-
yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-
amide were dissolved in 80 ml of carbon tetrachloride,
mixed with 1.5 g (8.4 mmol) of N-bromo-succinimide and 20
mg of azobisisobutyronitrile .and refluxed for 2.5 hours.
Then the still warm solution was filtered, the filtrate
obtained was washed with saturated sodium hydrogen
carbonate solution and dried with sodium sulphate. After
distillation of the solvent the crude product was dissolved
in 30 ml of N-ethyl-diisoprop:ylamine, mixed with 1.0 g
(8 mmol) of 4-aminobenzonitri:le and refluxed for 2.5 hours.
The solvent was distilled off in vacuo and the residue
obtained was purified by chromatography (silica gel; ethyl
acetate/petroleum ether = 1:4 to 1:1).
CA 02277949 1999-07-14
- 1.58 -
Yield: 1.1 g (30 % of theory),
Rf value: 0.21 (silica gel; a hyl acetate/petroleum ether =
1:1)
f. 1-Methyl-2-[N-(4-thiocarbamovl-phenyl)aminomethyll-
indol-5-yl-carboxylic acid-N-phenyl-N-(2-
methoxycarbonylethyl)-amide
1. 5 g ( 3 . 3 mmol ) of 2 - [N- ( 4 - cyanophenyl ) aminomethyl
] - indol -
5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-
amide were dissolved in 60 ml of xylene, mixed with 0.45 g
(3.3 mmol) of potassium carbonate and 0.5 ml of (3.3 mmol)
,,..,, of methyl p-toluenesulphonate and refluxed for 4 hours.
Then the same amounts of potassium carbonate and methyl
toluenesulphonate were added a second time and the mixture
was refluxed overnight. It was filtered and washed with
acetone. After concentration of the filtrate thus obtained,
the residue obtained was purified by chromatography (silica
gel; ethyl acetate/petroleum ether = 1:4 to 2:3). The
N-methylated indole obtained (yield: 0.64 g, 41 % of
theory) was dissolved in 20 m:1 of pyridine and mixed with
0.67 ml (1.37 mmol) of trietlzylamine. Then hydrogen
sulphide gas was introduced into the solution thus
obtained. After 4.5 days nitrogen was passed through the
reaction solution for 30 minutes, the solvent was distilled
off and the residue obtained was purified by chromatography
(silica gel; methylene chloride/ethanol 99:1 to 98:2).
Yield: 0.30 g (43 0 of theory) ,
C2gH2gN403S (500.62)
EKA mass spectrum: (M+H)+ - 501
(M+Na) + -- 523
g) 1-Methyl-2- [N- (4-amidinophe:nyl) aminomethyll -indol-5-yl-
carboxylic acid-N-phenyl-N-(2-~methoxvcarbonylethyl)-amide-
hydroiodide
0.30 g (0.60 mmol) of 1-methyl-2-[N-(4-thiocarbamoyl)-
phenyl)aminomethyl]-indol-5-yl.-carboxylic acid-N-phenyl-
N-(2-methoxycarbonylethyl)-amide were dissolved in 20 ml of
CA 02277949 1999-07-14
- 159 -
acetone together with 0.75 ml (12 mmol) of methyl iodide
and stirred for 2 hours at ambient temperature. Then the
solvent was distilled off and the crude product was stirred
together with 1.0 g of ammonium acetate in 12 ml of ethanol
and 5 ml of methylene chloride for 20 hours at 40°C. The
solvent was distilled off in vacuo and the residue obtained
was purified by chromatography (silica gel; methylene
chloride/ethanol = 9:1 to 4::1).
Yield: 55 % of theory,
C2gH29N503 (483.58)
Rf value: 0.20,'(silica gel; methylene chloride/ethanol =
'~ 4:1 + 1 drop of acetic acid)
EKA mass spectrum: (M+H) + = 484
Example 158
1-Methyl-2- [N- (4-amidinophenyl) aminomethyl] -
thieno[2.3-d]imidazol-5-yl-carboxylic acid-N-phenyl-N-(2-
ethoxycarbonylethyl)-amide-hydrochloride
a) Iminoethyl methoxyacetate hydrochloride
A solution of 35.5 g (0.50 me>1) of methoxyacetonitrile in
29 ml (23 g, 0:50 mol) of ethanol and 30 ml of absolute
,.-. diethylether was cooled to 0°C and over 1 hour 22.5 g
(0.62 mol) of hydrogen chloride gas was introduced, whilst
towards the end of the introduction of gas the reaction
product crystallised out. To complete the precipitation 130
ml of diethylether were added and the colourless needles
were filtered off.
Yield: 66.4 g (86 % of theory),
Melting point: 117-118°C.
b) 4-Hydroxymethyl-2-methoxymethyl-imidazole
A mixture of 30.6 g (0.20 mol) of iminoethyl
methoxyacetate-hydrochloride, 18 g (0.20 mol) of 1.3-
dihydroxyacetone and 200 ml of liquid ammonia was heated to
68°C for 3 hours in a stirred autoclave at a pressure of 27
CA 02277949 1999-07-14
- 1.60 -
bar (analogously to: P. Dziuron et al. Arch. Pharm. 307,
1974, p.470). Then the ammonia was eliminated and 200 ml of
methylene chloride were added. The white precipitate formed
was filtered off and washed with methylene chloride. The
filtrate was evaporated down and the residue obtained was
purified by chromatography (aluminium oxide; methylene
chloride/ethanol = 90:10 to 85:15).
Yield: 26.7 g (94 0 of theory),
Rf value: 0.43 (silica gel; methylene chloride/ethanol -
9:1)
C6H1pN202 (142.20)
'"~ Mass spectrum: (M)+ = 142
c) 4-Hydroxymethyl-2-methox~rm~=_thvl-1-methyl-imidazole as a
1:1 mixture with 5-hydroxymetlzyl-2-methoxymethyl-1-methyl
imidazole
A mixture of 7.1 g (50 mmol) of 4-hydroxymethyl-2-
methoxymethylimidazole, 3.0 g (53 mmol) of powdered
potassium hydroxide and 3.4 ml (0.55 mmol) of methyl iodide
was heated to 50°C in 100 ml of dimethylformamide for 4
hours (analogously to I. Sinc~~air et al., J. Med. Chem.,
29, 1986, 261). Then the solvent was distilled off in vacuo
and the crude product purified by column chromatography
,,..,. (aluminium oxide; methylene chloride/ethanol - 99:1 to
95:5).
Yield: 6.1 g (78 % of theory; 1:1 mixture of the two
regioisomers)
Rf value: 0.32 (silica gel; me:thylene chloride/ethanol =
19:1)
d) 5-Chloro-4-hvdroxvmethvl-2-methoxvmethvl-1-methvl
imidazole
A 1:1 mixture of 7.7 g (49 mmol) of 4-hydroxymethyl-
2-methoxymethyl-1-methyl-imidazole and 5-hydroxymethyl-
2-methoxymethyl-1-methyl-imidazole and 7.3 g (55 mmol) of
N-chloro-succinimide was heated to 50°C in 48 ml of
ethylene glycol monoethylether and 70 ml of dioxan for 10
CA 02277949 1999-07-14
- :L61 -
hours. Then the solvent was distilled off in vacuo and the
crude product purified by chromatography (silica gel;
methylene chloride/ethanol = 99:1 to 90:10) to obtain the
isomerically pure title compound.
Yield: 3.4 g (36 0 of theory),
Rf value: 0.40 (silica gel; nnethylene chloride/ethanol =
19:1)
e) 5-chloro-4-formyl-2-metho~:ymethyl-1-methyl-imidazole
3.4 g (18 mmol) of 5-chloro-9:-hydroxymethyl-2-
methoxymethyl-f-methyl-imida2:ole were dissolved in 100 ml
'" of methylene chloride and at two-hour intervals manganese
dioxide was added (2 x 6.0 g, a total of 0.14 mol). After 4
hours the inorganic component. was filtered off, the solvent
was eliminated and the crude product obtained was further
reacted without any further purification.
Yield: 3.0 g (89 0 of theory),
Rf value: 0.44 (silica gel; methylene chloride/ethanol =
50:1)
CA 02277949 1999-07-14
- 162 -
f) Ethyl 1-methyl-2-methoxymethyl-thieno[2.3-d]imidazol-5-
yl-carboxylate
To a freshly prepared sodium ethoxide solution (from
391 mg, 17 mMol of sodium) in 15 ml of ethanol were added
dropwise 1.9 ml (2.1 g, 17 mmol) of ethyl thioglycolate.
After 1 hour stirring at ambient temperature 1.6 g
(8.5 mmol) of 5-chloro-4-formyl-2-methoxymethyl-1-methyl-
imidazole in 20 ml of absolut=a ethanol were added and the
mixture was heated to 80°C (analogously to B. Iddon et al.,
J. Chem. Soc. Perkin Trans. :C, 1987, 1457). After 5 hours
the solvent was distilled ofi_, the residue was taken up in
50 ml of methylene chloride and washed with 20 ml of water.
The aqueous phase was washed again with 20 ml of methylene
chloride and then the combined organic phases were dried
with sodium sulphate. After removal of the solvent in vacuo
the crude product obtained was purified by column
chromatography (aluminium oxide; methylene chloride).
Yield: 1.0 g (46 0 of theory),
Rf value: 0.48 (silica gel; methylene chloride/ethanol =
50:1)
C11H14N2~3S (254.31)
EKA mass spectrum: (M+H)+ - 255
(M+Na)+ = 277
g) 1-Methyl-2-methoxymethyl-thieno[2.3-d]imidazol-5-yl-
carboxylic acid
To a solution of 0.90 g (3.54 mmol) of ethyl 1-methyl-2-
methoxymethyl-thieno[2.3-d]imidazol-5-yl-carboxylate in 30
ml of ethanol were added dropwise 5 ml of 2 N sodium
hydroxide solution and the mi:Kture was stirred for 2 hours
at ambient temperature. Then the solvent was distilled off
in vacuo, the residue was taken up in 5 ml of water and
washed with 10 ml of diethylei:her. The aqueous phase was
acidified with 6 ml of 2N hydrochloric acid, cooled to 0°C
and the precipitated crystals are filtered off.
Yield: 0.50 g (630 of theory)
CA 02277949 1999-07-14
- :163 -
Rf value: 0.21 (silica gel; rnethylene chloride/ethanol -
9:1 + a few drops of acetic acid)
CgH1pN203S (226.26)
Mass spectrum: (M)+ = 226
h) 1-Methyl-2-methoxymethyl-t:hieno [2 .3-d) imidazol-5-yl-
carboxylic acid-N=phenyl-N-(2-methoxycarbonylethyl)-amide
A suspension of 0.50 g (2.2 mmol) of 1-methyl-2-
methoxymethyl-thieno[2.3-d]imidazol-5-yl-carboxylic acid in
20 ml of methylene chloride was mixed with 2.0 ml (3.2 g,
27 mmol) of thionyl chloride and refluxed for 60 minutes,
during which time the solid gradually dissolved. After
distillation of the liquid components the crude product was
taken up twice more in methylene chloride. After the
solvent had been eliminated once more the crude acid
chloride was taken up in 20 ml of tetrahydrofuran and added
dropwise to a mixture of 0.42 g (2.3 mmol) of
N-(2-methoxycarbonylethyl)aniline and 0.92 ml (6.6 mmol) of
triethylamine in 30 ml of tetrahydrofuran. After 16 hours'
stirring at 50°C the solvent was eliminated and the crude
product obtained was purified by chromatography (silica
gel; methylene chloride/ethanol = 100:1).
Yield: 0.66 g (770 of theory),
Rf value: 0.47 (silica gel; methylene chloride/ethanol -
,..-.
19:1)
i) 1-Methyl-2-(N-4-cyanopheny:Laminomethyl)-
thienoC2.3-dlimidazol-5=yl-carboxylic acid-N-phenyl-N-(2-
methoxycarbonylethyl)-amide
To a solution of 0.73 g (1.88 mmol) of 1-methyl-2-
methoxymethyl-thieno[2.3-d]im_Ldazol-5-yl-carboxylic acid-N-
phenyl-N-(2-methoxycarbonylethyl)-amide in 30 ml of
methylene chloride were added dropwise at 5°C 2.9 ml (2.9
mmol) of a 1-molar solution of. boron tribromide in
methylene chloride. After 16 hours' stirring at ambient
temperature the mixture was washed with 20 ml of saturated
sodium hydrogen carbonate solution, the organic phase was
CA 02277949 1999-07-14
- 164 -
separated off, dried with sodium sulphate and filtered. The
filtrate was mixed with 14 m:1 of N-ethyl-diisopropylamine
and 0.43 g (3.64 mmol) of 4-aminobenzonitrile. Then the
methylene chloride was distilled off in vacuo, the residue
obtained was heated to 50°C :Eor 1 hour and then the
residual solvent was distilled off in vacuo. After
chromatography (silica gel; rnethylene chloride/ethanol =
99:1 to 97:3) a yellow oil was obtained which slowly
solidified.
Yield: 0.37 g (42% of theory),
Rf value: 0.29-~(silica gel; methylene chloride/ethanol =
"~ 50:1 + a few drops of ammonia )
j ) 1-Methyl-2- (N- (4-amidinophenyl) aminomethyl] -
thieno[2.3-d]imidazol-5-yl-carboxylic acid-N-phenyl-N-(2-
ethoxycarbonyleth~rl)-amide-hydrochloride
0.38 g (0.80 mmol) of 1-methyl-2-(N-4-
cyanophenylaminomethyl)-thieno[2.3-d]imidazol-5-yl-
carboxylic acid-N-phenyl-N-(2;-methoxycarbonylethyl)-amide
were stirred in 40 ml of ethanol saturated with hydrogen
chloride for 5 hours first at 0°C, then later at ambient
temperature until no more starting material could be
detected by thin layer chromatography. Then the solvent was
distilled off at a maximum 28°C bath temperature, the oily
residue was taken up in 40 ml of absolute ethanol and mixed
with 1.1 g of ammonium carbonate. After 18 hours the
solvent was distilled off in vacuo and the crude product
was purified by chromatography (silica gel; methylene
chloride/ethanol = 9:1 to 4:1).
Yield . 57 % of theory
C26H28N603S (504.62)
Rf value: 0.21 (silica gel; methylene chloride/ethanol =
4:1 + a few drops of acetic acid)
EKA mass spectrum: (M+H)+ - 505
(M+H+Na)++ = 264
CA 02277949 1999-07-14
- '.L65 -
Example 159
1-Methyl-2- [N- (4-amidinophenyl) aminomethyl] -
thieno[2.3-d)imidazol-5-yl-carboxylic acid-N-phenyl-N-(2-
hydroxycarbonylethyl)-amide-hydrochloride
Prepared analogously to Example 2 from 1-methyl-2-[N-(4-
amidinophenyl) aminomethyl] -th.ieno [2 . 3-d] imidazol-5-yl-
carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-
hydrochloride and sodium hydroxide solution.
Yield: 85 0 of theory,
'"' C24H24N603S (476.56)
Rf value: 0.36 (Reversed Phase silica gel RP-8; methanol
+ 5 o saline solution)
EKA mass spectrum: (M+H)+ - 477
(M+Na)+ - 499
(M+2Na) ++ = 250
Example 160
1-Methyl-3-[N-(4-amidinopheny:l)thiomethyl]-quinoxalin-2-on-
6-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-
amide-hydrochloride
a) 1-Methyl-3-[N-(4-cyanophem~l)thiomethyll-quinoxalin-2-
on-6-yl-carboxylic acid-N-phenyl-N-(2-
methoxycarbonvlethyl)-amide
A solution of 2.5 g (7.6 mmol) of 3-amino-4-methylamino-
benzoic acid-N-phenyl-N-(2-mei~hoxycarbonylethyl)-amide and
2.4 g (9.6 mmol) of ethyl 3-(4-cyanophenyl)thio-2-oxo-
propionate were heated to boiling in 50 ml of ethanol for
30 minutes. After removal of t:he solvent the crude product
obtained was purified by chrornatography (silica gel;
methylene chloride).
Yield: 1.6 g (40 0 of theory),
Rf value: 0.63 (silica gel; Et:OAc/EtOH/ammonia = 90:10:1)
CA 02277949 1999-07-14
- :L66 -
b) 1-Methyl-3-[N-(4-amidinophenyl)thiomethyl]-quinoxalin-2-
on-6-yl-carboxylic acid-N-phe:nyl-N-(2-ethoxycarbonylethyl)-
amide-hydrochloride
Prepared analogously to Example 1 from 1-methyl-3-[N-(4-
cyanophenyl)thiomethyl]-quinoxalin-2-on-6-yl-carboxylic
acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide and ethanolic
hydrochloric acid, ethanol anal ammonium carbonate.
Yield: 23 % of theory,
C28H2~N504S (543.64)
Rf value: 0.25,~(silica gel; ethyl acetate/ethanol/ammonia
~ - 50:45:5)
EKA mass spectrum: (M+H)+ - 544
(M+Na)+ = 566
Example 161
3-Methyl-2- [2- (4-amidinopheny:l) ethyl] -
imidazo [1. 2-a] pyridin-7-yl-ca:rboxylic acid-N-phenyl-N- (2-
ethoxycarbonylethyl)-amide-hydrochloride
a) 3-Methyl-2- 2- (4-cvanophen~,rl) ethvll -
imidazo 1.2-alpyridin-7-yl-ca~~boxvlic acid-N-phenyl-N-(2-
,,,... ethoxycarbonylethyl ) -amide
1 .4 g (4 .6 mmol) of 3-methyl-2- [2- (4-cyanophenyl) ethyl] -
imidazo[1.2-a]pyridin-7-yl-carboxylic acid (prepared from
4-bromo-1-(4-cyanophenyl)-1-pe:nten-3-one and methyl 2-
aminopyridine-4-carboxylate analogously to Y. Katsura et
al. Chem. Pharm. Bull. 1992, 9:0, 1424-1438) were suspended
in 15 ml of thionyl chloride amd heated to boiling for 1
hour until fully dissolved. After the thionyl chloride had
been distilled off the acid chloride was dissolved in l5 ml
of pyridine without any further purification and at 0
mixed with 1.0 g (5.2 mmol) of N-(2-ethoxycarbonylethyl)-
aniline. After 1 hour the solvent was distilled off, the
residue was taken up in 30 ml of methylene chloride, washed
with 15 ml of 1N hydrochloric acid and dried with sodium
CA 02277949 1999-07-14
- 167 -
sulphate. After distillation of the solvent and
chromatography (silica gel; methylene chloride/ethanol - 0
to 2 %) a brown oil was obtained.
Yield: 1.48 g (64 0 of theory),
Rf value: 0.73 (silica gel; ethyl acetate/ethanol/ammonia =
90:10:1)
b) 3-Methyl-2- [2- (4-amidinoph~enyl) ethyll -
imidazo[1.2-a]pyridin-7-yl-ca:rboxylic acid-N-phenyl-N-(2-
ethoxycarbonylethyl)-amide-hydrochloride
Prepared analogously to Example 1 from 3-methyl-2-[2-(4-
a~ cyanophenyl)ethyl]-imidazo[1.:2-a]pyridin-7-yl-carboxylic
acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide and ethanolic
hydrochloric acid, ethanol and ammonium carbonate.
Yield: 62 % of theory,
C29H31N5~3 (497.60)
Rf value: 0.23 (silica gel; ei=hyl acetate/ethanol/ammonia
- 50:45:5)
EKA mass spectrum: (M+H) + = 4!38
Example 162
3-Methyl-2- [2- (4-amidinophenyl) ethyl] -
,,...... imidazo [1.2-a] pyridin-7-yl-carboxylic acid-N-phenyl-N- (2-
hydroxycarbonylethyl)-amide-hydrochloride
Prepared analogously to Examp7_e 2 from 3-methyl-2-[2-(4-
amidinophenyl)ethyl]-imidazo[7_.2-a]pyridin-7-yl-carboxylic
acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride
and sodium hydroxide solution.
Yield: 92 a of theory,
C27H27N5~3 (469.55)
Rf value: 0.19 (silica ge:l; ethyl
acetate/ethanol/ammonia - 50:45:5)
EKA mass spectrum: (M+H)+ - 470
(M+Na) + - 492
CA 02277949 1999-07-14
- :168 -
(M+2H) ++ - 235 . 7
(M+H+Na)-~+ = 246.7
(M+2Na) +-~ - 257 . 7
Example 163
1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-
5-yl-carboxylic acid-N-phenyl.-N-[(N-ethoxycarbonylethyl-N-
methyl)-2-aminoethyl]-amide-clihydrochloride
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-
cyanophenyl)-aminomethyl]-ben.zimidazol-5-yl-carboxylic
acid-N-phenyl-N-[(N-ethoxycarbonylethyl-N-methyl)-2-
aminoethyl]-amide and ethanolic hydrochloric acid, ethanol
and ammonium carbonate.
Yield: 80 % of theory,
C31H37N7~3 (555.7)
Rf value: 0.24 (silica gel; dichloromethane/methanol = 4:1)
EKA mass spectrum: (M+H)+ - 556
2 0 ( M+H+Na ) ++ = 2 8 9 . 8
(M+2H) ++ - 278 . 8
Example 164
1-Methyl-2-[N-(4-amidinopheny:l)-aminomethyl]-benzimidazol-
5-yl-carboxylic acid-N-phenyl-N-[(N-hydroxycarbonylethyl-N-
methyl)-2-aminoethyl]-amide-hydrochloride
Prepared analogously to Example 26 from 1-methyl-2-[N-(4-
amidinophenyl)-aminomethyl]-be~nzimidazol-5-yl-carboxylic
acid-N-phenyl-N-[(N-ethoxycarbonylethyl-N-methyl)-2-
aminoethyl]-amide-dihydrochloride and sodium hydroxide
solution.
Yield: 79 0 of theory,
C2gH33N703 (527.6)
CA 02277949 1999-07-14
- 1.69 -
Rf value: 0.43 (Reversed, Phase silica gel RP-18;
methanol/5% aqueous saline solution = 6:4)
EKA mass spectrum: (M+H)+ - 528
(M+H+Na)++ = 275.6
(M+2H) ++ - 264 . 6
Example 165
1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-
5-yl-carboxylic acid-N-phenyl-N-(3-hydroxy-n-propyl)-amide-
hydrochloride
Prepared from 1-methyl-2-(N-(4-amidinophenyl)-aminomethyl]-
benzimidazol-5-yl-carboxylic .acid-N-phenyl-N-(3-benzyloxy-
n-propyl)-amide-hydrochloride by hydrogenation over
palladium/charcoal (10%) at 5 bar hydrogen pressure and at
ambient temperature.
Yield: 61 % of theory,
C26H28N602 (456.6)
Rf value: 0.70 (Reversed Phass~ silica gel RP-18;
methanol/5% aqueous saline so:Lution = 9:1)
EKA mass spectrum: (M+H)+ - 457
( M+H+Na ) +-~ = 2 4 0
CA 02277949 1999-07-14
' - 170 -
Example 166
1-Methyl-2- [N- (4- (N-n-hexylo:~cycarbonylamidino)phenyl] -
aminomethyl]-benzimidazol-5-girl-carboxylic acid-N-(2-
pyridyl)-N-(2-hydroxycarbonylethyl)-amide
Prepared analogously to Example 26 from 1-methyl-2-(N-[4-
(N-n-hexyloxycarbonylamidino)phenyl]-aminomethyl]-
benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-
ethoxycarbonylethyl)-amide and sodium hydroxide solution.
Yield: 97 % of~theory,
~~ C32H37N7~5 (599.7)
Rf value: 0.22 (silica gel; dichloromethane/methanol = 9:1)
EKA mass spectrum: (M+H)+ - 600
(M+H+Na)+'+ = 311.7
(M+2H)++ - 300.8
(M+2Na)++ - 322.8
Example 167
1-Methyl-2-[N-(4-(N-n-hexyloxycarbonylamidino)phenyl]-
aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-
(3-hydroxy-n-propyl)-amide
Prepared analogously to Example 165 from 1-methyl-2-[N-[4-
(N-n-hexyloxycarbonylamidino);phenyl] -aminomethyl] -
benzimidazol-5-yl-carboxylic .acid-N-phenyl-N-(3-benzyloxy-
n-propyl)-amide by catalytic debenzylation.
Yield: 26 0 of theory,
C33H40N604 (584.7)
Rf value: 0.39 (silica gel; d:ichloromethane/ethanol = 9:1 )
EKA mass spectrum: (M+H)+ - 585
(M+H+Na) +~+ = 304
(M+Na) + - 607
CA 02277949 1999-07-14
- 1.71 -
Example 168
1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-
5-yl-carboxylic acid-N-(3-flu.orophenyl)-N-(2-
ethoxycarbonylethyl)-amide-hydrochloride
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-
cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic
acid-N-(3-fluorophenyl)-N-(2-ethoxycarbonylethyl)-amide and
ethanolic hydrochloric acid, ethanol and ammonium
carbonate.
,.-" Yield: 42 0 of theory,
C28H29FN6~3 (516.6)
Rf value: 0.31 (silica gel; dichloromethane/methanol = 5:1)
EKA mass spectrum: (M+H)+ - 517
( M+H+Na ) +'+ - 2 7 0
Example 169
1-Methyl-2-[N-(4-amidinopheny:L)-aminomethyl]-benzimidazol-
5-yl-carboxylic acid-N-(4-fluorophenyl)-N-(2-
ethoxycarbonylethyl)-amide-hydrochloride
~- Prepared analogously to Examp:Le 25d from 1-methyl-2-[N-(4-
cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic
acid-N-(4-fluorophenyl)-N-(2-eahoxycarbonylethyl)-amide and
ethanolic hydrochloric acid, ethanol and ammonium
carbonate.
Yield: 90 % of theory,
C2gH2gFN603 (516.6)
Rf value: 0.29 (silica gel; dichloromethane/methanol = 5:1)
EKA mass spectrum: (M+H)+ - 517
(M+H+Na) +~- - 270
CA 02277949 1999-07-14
- :172 -
Example 170
1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-
5-yl-carboxylic acid-N-(3-fluorophenyl)-N-(2-
hydroxycarbonylethyl)-amide
Prepared analogously to Example 26 from 1-methyl-2-[N-(4-
amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic
acid-N-(3-fluorophenyl)-N-(2--ethoxycarbonylethyl)-amide-
hydrochloride and sodium hydroxide solution.
Yield: 97 % of,theory,
,,... C26H25FN6~3 (488.5)
Rf value: 0.13 (silica gel; dichloromethane/ethanol = 4:1)
EKA mass spectrum: (M+H)+ - 489
( M+Na ) + - 511
(M+2Na) ++' - 267
Example 171
1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-
5-yl-carboxylic acid-N-(4-fluorophenyl)-N-(2-
hydroxycarbonylethyl)-amide
..... Prepared analogously to Example 26 from 1-methyl-2- [N- (4-
amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic
acid-N-(4-fluorophenyl)-N-(2-ethoxycarbonylethyl)-amide-
hydrochloride and sodium hydroxide solution.
Yield: 89 % of theory,
C26H25FN6~3 (488.5)
Rf value: 0.15 (silica gel; dichloromethane/ethanol = 4:1)
EKA mass spectrum: (M+H)+ - 489
(M+Na)+ - 511
(M+2Na)++ = 267
CA 02277949 1999-07-14
- 173 -
Example 172
1-Methyl-2-[N-(4-amidino-2-methoxy-phenyl)-aminomethyl]-
benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-
ethoxycarbonylethyl)-amide-hydrochloride
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-
cyano-2-methoxy-phenyl)-aminomethyl)-benzimidazol-5-yl-
carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide
and ethanolic hydrochloric acid, Esthanol and ammonium
carbonate.
-,.
Yield: 89 % of theory,
C29H32N6~4 (528.6)
Rf value: 0.13 (silica gel; dichloromethane/ethanol = 4:1)
EKA mass spectrum: (M+H) + - ~>29
( M+H+Na ) ++ _ ~: 7 6
(M+2H) ++ - 2 65
Example 173
1-Methyl-2-[N-[4-(N-4-ethylbenzoylamidino)phenyl)-
aminomethyl)-benzimidazol-5-yl-carboxylic acid-N-(2-
,,-. pyridyl)-N-(2-ethoxycarbonylethyl)-amide
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-
amidinophenyl)-aminomethyl)-benzimidazol-5-yl-carboxylic
acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-
hydrochloride and 4-ethylbenzoylchloride.
Yield: 64 % of theory,
C36H37N7~4 (631.7)
Rf value: 0.78 (silica gel; dichloromethane/methanol = 9:1)
EKA mass spectrum: (M+H)+ - 6:32
( M+H+Na ) ++ = 3 2 7 . 8
(M+Na) + - 654
CA 02277949 1999-07-14
- 174 -
1-Methyl-2- [N- [4- (N-benzyloxycarbonylamidino) phenyl] -
aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-
pyridyl)-N-(2-ethoxycarbonylethyl)-amide
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-
amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic
acid-N-(2-pyridyl)-N-(2-ethox:ycarbonylethyl)-amide-
hydrochloride and benzyl chloroformate.
Yield: 64 % of theory,
C35H35N7~5 (633.6)
Rf value: 0.60 (silica gel; d.ichloromethane/methanol = 9:1)
EKA mass spectrum: (M+H)+ - 634
(M+H+Na)++ = 328.8
(M+Na)+ - 656
1-Methyl-2-[N-(4-amidino-2-methoxy-phenyl)-aminomethyl]-
benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-
hydroxycarbonylethyl)-amide
Prepared analogously to Example 26 from 1-methyl-2-[N-(4-
amidino-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl-
carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-
hydrochloride and sodium hydroxide solution.
Yield: 71 % of theory,
C27H28N604 (500.6)
Rf value: 0.15 (silica gel; dichloromethane/ethanol = 4:1)
EKA mass spectrum: (M+H)+ - 501
(M+Na) + - 523
(M+2Na)++ = 273
CA 02277949 1999-07-14
- 175 -
Example 176
1-Methyl-2-[N-(4-amidino-2-methoxy-phenyl)-aminomethyl]-
benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-
ethoxycarbonylethyl)-amide-hydrochloride
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-
cyano-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl-
carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-
amide and ethanolic hydrochloric acid, ethanol and ammonium
carbonate.
Yield: 67 % of/theory,
C28H31N7~4 (529.6)
Rf value: 0.16 (silica gel; dichloromethane/ethanol - 4:1)
EKA mass spectrum: (M+H) + _ ~>30
CA 02277949 1999-07-14
- 1.76 -
Example 177
1-Methyl-2-[N-(4-amidino-2-me hoxy-phenyl)-aminomethyl]-
benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-
hydroxycarbonylethyl)-amide
Prepared analogously to Example 26 from 1-methyl-2-[N-(4-
amidino-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl-
carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-
amide-hydrochloride and sodium hydroxide solution.
Yield: 78 % of theory,
~- C26H27N7~4 (501.6)
Rf value: 0.12 (silica gel; dichloromethane/ethanol = 4:1)
EKA mass spectrum: (M+H)+ = 502
Example 178
1-Methyl-2- [N- [4- (N-benzyloxycarbonylamidino) phenyl] -amino-
methyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-
(2-hydroxycarbonylethyl)-amide
Prepared analogously to Example 104 from 1-methyl-2-[N-[4-
(N-benzyloxycarbonylamidino)phenyl]-aminomethyl]-
benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-
ethoxycarbonylethyl)-amide and sodium hydroxide solution.
Yield: 62 % of theory,
C33H31N7~5 (605.7)
Rf value: 0.26 (silica gel; dichloromethane/methanol = 9:1)
EKA mass spectrum: (M+H)+ - 606
(M+Na) + - 628
(M-H+2Na) ~- - 650
(M+2H)++ - 303.8
(M+H+Na) +~~ - 314 . 8
(M+2Na)++ - 325.7
CA 02277949 1999-07-14
- 177 -
Example 179
1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-
5-yl-carboxylic acid-N-phenyl-N-(3-benzyloxy-n-propyl)-
amide-hydrochloride
Prepared analogously to Example 25 from 1-methyl-2-[N-(4-
cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic
acid-N-phenyl-N-(3-benzyloxy--n-propyl)-amide and ethanolic
hydrochloric acid, ethanol and ammonium carbonate.
Yield: 61 % of~theory,
C33H34N602 (546.7)
Rf value: 0.19 (silica gel; clichloromethane/ethanol = 4:1)
EKA mass spectrum: (M+H)+ - 547
(M+H+Na)+'+ = 285
Example 180
1-Methyl-2- [N- [4- (N-n-hexylox:ycarbonylamidino)phenyl] -
aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-
(3-benzyloxy-n-propyl)-amide
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-
amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic
,~-~ acid-N-phenyl-N-(3-benzyloxy-n-propyl)-amide-hydrochloride
and n-hexyl chloroformate.
Yield: 73 % of theory,
C40H46N6~4 (674.9)
Rf value: 0.46 (silica gel; dichloromethane/ethanol = 9:1)
EKA mass spectrum: (M+H)+ - 675
(M+H+Na)++ = 349
(M+Na) + - 697
(M+K)+ - 713
CA 02277949 1999-07-14
- :178 -
Example 181
3-Methyl-2- [2- (4-amidinophenyl) ethyl] -
imidazo[1.2-a]pyridin-7-yl-carboxylic acid-N-(2-pyridyl)-N-
(2-ethoxycarbonylethyl)-amide'-hydrochloride
Prepared analogously to Example 1 from 3-methyl-2-[2-(4-
cyanophenyl)ethyl]-imidazo[1.2-a]pyridin-7-yl-carboxylic
acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide-
hydrochloride and ethanolic hydrochloric acid, ethanol and
ammonium carbonate.
,.... Yield : 53 % of theory,
C28H30N6~3 (498.59)
Rf value: 0.42 (silica gel; ethyl acetate/ethanol/ammonia
- 50:45:5)
EKA mass spectrum: (M+H)+ - 499
(M+2Na)++ - 272
(M+H+Na)++ = 261
(M+2H)++ - 250
Example 182
1-Methyl-2-[N-(3-amidino-pyridin-6-yl)-aminomethyl]-
'"" benzimidazol-5-yl-carboxylic .acid-N-(2-pyridyl)-N-(2-
hydroxycarbonylethyl)-amide
Prepared analogously to Example 26 from 1-methyl-
2-[N-(3-cyanopyridin-6-yl)-am:inomethyl]-benzimidazol-5-yl-
carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-
amide and sodium hydroxide solution.
Yield: 40 % of theory,
C24H24N8~3 (472.9)
Rf value: 0.67 (Reversed Phase silica gel RP-8; methanol/5%
saline soluti0I1 = 1:1)
EKA mass spectrum: (M+H) + = 4'73
CA 02277949 1999-07-14
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Example 183
1-Methyl-2- [N- [4- (N-hydroxylamidino) phenyl] -aminomethyl] -
benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-[2-
(methansulphonylaminocarbonyl)-ethyl]-amide
a. 1-Methyl-2-fN-(4-cyanopherwl)-aminomethyll-benzimidazol-
5-yl-carbox~rlic acid-N- (2 =pyridyl) -N- f2-
(methanesulphonylaminocarbonyl)-ethyl]-amide
2.0 g (4.5 mmol) of 1-methyl-2-[N-(4-cyanophenyl)-
aminomethyl]-benzimidazol-5-yl-carboxylic acid-
N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide and 0.73 g
(4.7 mmol) of carbonyldiimida.zole were dissolved in 80 ml
of tetrahydrofuran and 5 ml of dimethylformamide and
stirred for 30 minutes at ambient temperature and for
2 hours at 90°C. In parallel 0.55 g (5.8 mmol) of
methansulphonic acid amide and 0.28 g (5.8 mmol) of sodium
hydride were suspended in 15 ml of dimethylformamide and
stirred for 2 hours at ambient temperature. Then this
suspension was added at ambient temperature to the
tetrahydrofuran solution. After 12 hours at ambient
temperature 50 ml of water were added and the pH value was
adjusted to 6.8. The solution was extracted 4x with
methylene chloride, the combined organic phases were dried
-- 25 over sodium sulphate and evaporated down. The crude product
was chromatographed on silica gel (methylene
chloride/ethanol (40:1)). The desired fractions were
combined and evaporated down. Yield: 1.05 g (44 0 of
theory) ,
C26H25N7~4S (531.6)
Rf value: 0.72 (silica gel; d:ichloromethane/methanol = 9:1)
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b. 1-Methvl-2-[N-f4-(N-hydroxylamidino)phenyll-
aminomethvll-benzimidazol-5-yl-carboxylic acid-
N-(2-pvridyl)-N- 2-(methansu'Lphonvlaminocarbonyl)-ethyll-
amide
Prepared analogously to Example 96 from 1-methyl-
2- [N- (4-cyanophenyl) -aminomei:hyl] -benzimidazol-5-yl-
carboxylic acid-N-(2-pyridyl)-N-[2-
(methanesulphonylaminocarbonyl)-ethyl]-amide and
hydroxylamine.
Yield: 27% of theory,
°~~ C26H2gN805S (564.6)
Rf value: 0.75 (silica gel; dichloromethane/ethanol = 7:3 +
1% glacial acetic acid)
EKA mass spectrum: (M+H)+ - 565
(M+Na)' _ ~~87
Example 184
1-Methyl-2-[N-(5-amidino-thia.zol-2-yl)-aminomethyl]-
benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-
ethoxycarbonylethyl)-amide-hydrochloride
,,.~ Prepared analogously to Example 25d from 1-methyl-
2-[N-(5-cyano-thiazol-2-yl)-aminomethyl]-benzimidazol-5-yl-
carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-
amide and ethanolic hydrochloric acid, ethanol and ammonium
carbonate.
Example 185
1-Methyl-2-[N-(5-amidino-thia:zol-2-yl)-aminomethyl]-
benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-
hydroxycarbonylethyl)-amide
Prepared analogously to Example 26 from 1-methyl-
2-[N-(5-amidino-thiazol-2-yl)--aminomethyl]-benzimidazol-
CA 02277949 1999-07-14
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5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-
ethoxycarbonylethyl)-amide-hydrochloride and sodium
hydroxide solution.
Example 186
1-Methyl-2-[N-(2-amidino-pyrazin-5-yl)-aminomethyl]-
benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-
ethoxycarbonylethyl)-amide-hydrochloride
Prepared analogously to Example 25d from 1-methyl-
2-[N-(2-cyano-pyrazin-5-yl)-aminomethyl]-benzimidazol-5-yl-
carboxylic acid-N-(2-pyridyl>-N-(2-ethoxycarbonylethyl)-
amide and ethanolic hydrochloric acid, ethanol and ammonium
carbonate.
Yield: 19 0 of theory,
C25H27N9~3 (501.6)
Rf value: 0.28 (silica gel; dichloromethane/methanol = 4:1
+ 1% glacial acetic acid)
EKA mass spectrum: (M+H)+ - 502
(M+H+Na)'~ = 262.5
Example 187
1-Methyl-2-[N-(2-amidino-pyrazin-5-yl)-aminomethyl]-
benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-
hydroxycarbonylethyl)-amide
Prepared analogously to Example 26 from 1-methyl-
2-[N-(2-amidino-pyrazin-5-yl)-aminomethyl]-benzimidazol-
5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-
ethoxycarbonylethyl)-amide-hydrochloride and sodium
hydroxide solution.
Yield: 11 % of theory,
C23H23N9~3 (473.5)
CA 02277949 1999-07-14
- :L82 -
Rf value: 0.55 (Reversed Phase silica gel RP-8; 5% saline
solution/methanol = 6:4)
EKA mass spectrum: (M+H)+ - 474
( M+H+Na ) ~- - 4 9 6 . 6
Example 188
1-Methyl-2- [2- [4- (N-n-hexylo~ycarbonylamidino) phenyl] -
ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[2-
(1H-tetrazol-5-yl)-ethyl]-amide
,.-
Prepared analogously to Example 90 from 1-methyl-2-[2-(4-
amidinophenyl)-ethyl]-benzimi.dazol-5-yl-carboxylic acid-
N-phenyl-N-[2-(1H-tetrazol-5-yl)-ethyl]-amide and n-hexyl
chloroformate.
Example 189
1-Methyl-2-[N-(2-methoxy-4-n-pentoxycarbonylamidino
phenyl)-aminomethyl]-benzimid.azol-5-yl-carboxylic acid-N
phenyl-N-(2-ethoxycarbonyleth.yl)-amide
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-
~- amidino-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl-
carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-
hydrochloride and n-pentyl chloroformate.
Yield: 53 % of theory,
C3 SH42~'T6~6 ( 642 . 7 )
Rf value: 0.54 (silica gel; dichloromethane/ethanol = 9:1 )
EKA mass spectrum: (M+H)+ - 643
(M+H+Na)++ = 333.4
CA 02277949 1999-07-14
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Example 190
1-Methyl-2-[N-(4-n-heptyloxycarbonylamidino-2-methoxy-
phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-
phenyl-N-(2-ethoxycarbonyletlzyl)-amide
Prepared analogously to Example 90 from 1-methyl-2-[N-(4
amidino-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl
carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide
hydrochloride and n-heptyl chloroformate.
Yield: 68 % of,~ theory,
'"' C37H46N606 (670.8)
Rf value: 0.56 (silica gel; dichloromethane/ethanol = 9:1 )
EKA mass spectrum: (M+H)+ - 671
( M+H+Na ) 'c-+ = 3 4 7 . 4
Example 191
1-Methyl-2-[N-(4-ethoxycarbor~ylamidino-2-methoxy-phenyl)-
aminomethyl]-benzimidazol-5-~~1-carboxylic acid-N-(2-
pyridyl)-N-(2-ethoxycarbonyleahyl)-amide
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-
A~ amidino-2-methoxy-phenyl)-ami.nomethyl]-benzimidazol-5-yl-
carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-
amide-hydrochloride and ethyl chloroformate.
Yield: 43 % of theory,
C31H35N706 (601.7)
Rf value: 0.44 (silica gel; d.ichloromethane/ethanol = 9:1)
EKA mass spectrum: (M+H)+ - 602
(M+H+Na)++ = 312.8
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- :L 8 4 -
Example 192
1-Methyl-2-[N-(2-methoxy-4-n~-pentoxycarbonylamidino-
phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-
(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-
amidino-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl-
carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-
amide-hydrochloride and n-pentyl chloroformate.
Yield: 72 % of theory,
'""" C34H41N7~6 (643.7)
Rf value: 0.49 (silica gel; dichloromethane/ethanol = 9:1)
EKA mass spectrum: (M+H)+ - 644
(M+H+Na)+'+ = 333.9
Example 193
1-Methyl-2-[N-(2-methoxy-4-n-heptyloxycarbonylamidino-
phenyl)-aminomethyl]-benzimid.azol-5-yl-carboxylic acid-N-
(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-
amidino-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl-
carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-
amide-hydrochloride and n-heptyl chloroformate.
Yield: 55 % of theory,
C36H45rT7~6 (671.8)
Rf value: 0.54 (silica gel; dichloromethane/ethanol = 9:1)
EKA mass spectrum: (M+H)+ - 672
( M+H+Na ) ++ = 3 4 7 . 9
CA 02277949 1999-07-14
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Example 194
Dry ampoule containing 75 mg of active substance per 10 ml
Composition:
Active substance 75.0 mg
Mannitol 50.0 mg
water for injections ad 10.0 ml
.~-~ Preparation
Active substance and mannito7_ are dissolved in water.
After packaging the solution is freeze-dried. To produce
the solution ready for use, t:he product is dissolved in
water for injections.
CA 02277949 1999-07-14
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Example 195
Dry ampoule containing 35 mg of active substance per 2 ml
Composition:
Active substance 35.0 mg
Mannitol 100.0 mg
water for injections ad 2.0 ml
Preparation:
Active substance and mannito7_ are dissolved in water. After
packaging, the solution is freeze-dried.
To produce the solution ready for use, the product is
dissolved in water for injections.
Example 196
Tablet containing 50 mg of active substance
Composition:
(1) Active substance 50.0 mg
(2) Lactose 98.0 mg
(3) Maize starch 50.0 mg
(4) Polyvinylpyrrolidone 15.0 mg
(5) Magnesium stearate 2.0 mq
215.0 mg
Preparation:
(1), (2) and (3) are mixed together and granulated with an
aqueous solution of (4). (5) is added to the dried
granulated material. From this mixture tablets are pressed,
CA 02277949 1999-07-14
- 187 -
biplanar, faceted on both sides and with a dividing notch
on one side.
Diameter of the tablets: 9 mm.
Example 197
Tablet containing 350 mg of active substance
Preparation:
(1) Active substance 350.0 mg
(2) Lactose 136.0 mg
(3) Maize starch 80.0 mg
(4) Polyvinylpyrrolidone 30.0 mg
(5) Magnesium stearate 4.O mct
600.0 mg
(1), (2) and (3) are mixed together and granulated with an
aqueous solution of (4). (5) is added to the dried
granulated material. From this mixture tablets are
pressed, biplanar, faceted on both sides and with a
dividing notch on one side.
Diameter of the tablets: 12 mm.
~'~ 2 5
Example 198
Capsules containing 50 mg of active substance
Composition:
(1) Active substance 50.0 mg
(2) Dried maize starch 58.0 mg
(3) Powdered lactose 50.0 mg
(4) Magnesium stearate 2.0 ma
160.0 mg
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- 188 -
Preparation:
(1) is triturated with (3). This trituration is added to
the mixture of (2) and (4) with vigorous mixing.
This powder mixture is packed into size 3 hard gelatin
capsules in a capsule filling machine.
Example 199
Capsules containing 350 mg of active substance
Composition:
(1) Active substance 350.0 mg
(2) Dried maize starch 46.0 mg
(3) Powdered lactose 30.0 mg
(4) Magnesium stearate 4.0 mct
430.0 mg
Preparation:
(1) is triturated with (3). This trituration is added to
the mixture of ( 2 ) and ( 4 ) with vigorous mixing .
This powder mixture is packed into size 0 hard gelatin
""~ 25 capsules in a capsule filling machine.
Example 200
Suppositories containing 100 mg of active substance
1 suppository contains:
Active substance 100.0 mg
Polyethyleneglycol (M.W. 1500) 600.0 mg
Polyethyleneglycol (M.W. 6000) 460.0 mg
Polyethylenesorbitan monostearate 840.0 ma
2,000.0 mg
