Note: Descriptions are shown in the official language in which they were submitted.
Boehringer Ingelheim Pharma KC Case 5/1320-Niah
J=552y?~3 IngelheimlRhein Foreign filing text
78131 ff.206
Substituted aryl and heteroaryi derivatives, the preparation thereof and
the use thereof as pharmaceutical compositions
Substituted aryl and heteroaryl derivatives with an antithrombotic effect are
already
known from WO 00/35859.
The present invention relates to new substituted aryl and heteroaryl
derivatives of
general formula ~l)
~o
Ar-A-(CH2)" (CHR~ )- X--~~ ~ Y-0,
Y
R'' ~ ~l)
the prodrugs, the tautomers, the stereoisomers, the mixtures and the salts
thereof,
particularly the physiologically acceptable salts thereof ~nrith inorganic or
organic acids
~ 5 or bases, which have valuable properties.
The compounds of the above general formula I wherein R5 does not contain a
cyano
group, have valuable pharmacological properties, particularly an
antithrombotic effect
and a selective factor Xa-inhibiting effect, and
the compounds of the above general formula I wherein R5 contains a cyano
group,
constitute valuable intermediate products for preparing the compounds of
general
formula I wherein R~ denotes an optionally substituted arnidino group.
The present invention thus relates to new compounds of the above general
formula I as
well as the preparation thereof, the pharmaceutical compositions containing
the
pharmacologically effective compounds and the use thereof.
CA 02445571 2003-10-29
-2-
In the above general formula I
A denotes an ethynylene or an ethylene group,
n denotes one of the numbers 0 or 1,
R~ denotes a hydrogen atom, a C~_3-alkyl, carboxy-C~_3-alkyl, phenyl, phenyl-
C~_3-alkyl,
heteroaryl, heteroaryl-C~_3-alkyl, N-C~_3-alkylaminocarbonyl-C~_3-alkyl, N,N-
DI-(C~_3-
alkyl)-aminocarbonyl-C~.3-alkyl or C~._7-cycloalkyieneimino-carbonyl-C~_3-
alkyl group,
Ar denotes a phenyl or pyridyl group substituted by the groups R2 to R4, while
R2 denotes a C~_6-alkyl or C3_rcycloalkyl-C~_3-alkyl group, while the acyclic
alkyl
moieties thereof may be substituted in each case by a carboxy, amino, C~-3-
alkylamino, carboxy-C~_3-alkylamino, di-(C1_3-alkyl)-amino, pyrrolidino,
piperidino,
hexamethyleneimino, N-(carboxy-C9_3-alkyl)-C~_3-alkylamrno Or C3_7-
cycloalkylamino
group,
a carboxy-C~_5-alkyl group which is substituted in the alkyl moiety by a C~_3-
2o alkylamino, N,N-di-(C~_3-alkyl)-amino, pyrrolidino, piperidino or
hexamethyleneimino
group,
a carboxy-C~_5-alkyl group wherein the hydrogen atoms of a methylene group are
replaced by a n-C2_5-alkylene bridge,
a phenyl or heteroaryl group which may additionally be substituted in each
case by a
fluorine, chlorine, bromine or iodine atom, by a trifluoromethyl, C1_3-alkyl,
carboxy-
C~_3-alkyl, C~_3-alkoxy, C~_3-alkylsulphonyl, aminosuiphonyl, C~_3-
alkylaminosulphonyl
or di-(C~_3-alkyl)-aminosuiphonyl group,
CA 02445571 2003-10-29
-
a C~_5-alkylamino, carboxy-C~_3-alkylamino, di-(C~_5-alkyl)-amino, N-(carboxy-
C,_3-
alkyl)-C~_~-alkylamino, Cs_7-cycioalkylamino or N-(carboxy-C~_3-alkyl)-C3_7-
cycloalkylamino group,
a C3_~-cycloalkylcarbonylamino, N-(C~_3-alkyl)-C~_5-alkylcarbonylamino or N-
(C~_3-
a(kyl)-C~7-cycloalkylcarbonylamino group, while
the abovementioned N-(C~_3-alkyl) moieties may additionally be substituted by
a
carboxy, carboxy-C~_3-alkylaminocarbonyl or lt!-(C~_3-alkyl)-carboxy-C~_3-
alkylaminocarbonyl group or, with the exception of the ~,-carbon atom based on
the nitrogen atom, may also be substituted by a hydroxy, carboxy-C~_3-alkoxy,
amino, carboxy-C~_3-alkylamino or N-(C~_3-alkyl)-carboxy-C~_3-alkylamino
group,
a 5- to 7-membered cycloalkyleneimino group,
an amino, C~_~-alkylamino or C3_7-cycloalkylamino group which is substituted
in each
case at the amino-nitrogen atom by a C~_5-alkylcarbonyl, carboxy-C~_3-
alkylcarbonyl
or carboxy-C~_3-alkylaminocarbonyl group, while additionally
2o the alkyl moiety of the abovementioned C~_5-alkylcarbonyl- and carboxy-C~_3-
alkylcarbonyl group may be substituted by an amino, hydroxy, carboxy-C~_3-
alkoxy,
carboxy-C,_3-alkylaminocarbonyl, carboxy-C1.~-alkylamino, N-(C~_3-alkyl)-
carboxy-
C~_3-alkylamino or amino-C~_3-alkylcarbonylamino group,
a carbonyl group which is substituted
by a C~_5-alkyl or C~7-cycloalkyf group optionally substituted by a carboxy
group,
by a phenyl group which may be substituted by a fluorine, chlorine, bromine or
so iodine atom, by a C~_3-alkyl, carboxy-C~_3-alkyl, C~_3-alkoxy, carboxy,
C~_3-alky!-
sulphonyl, aminosulphonyl, C~_3-alkylaminosulphonyl, di-(C1_3-alkyl)-amino-
sulphonyl group,
CA 02445571 2003-10-29
,-
by an amino, C~_~-alkylamino, C2_~-alkenylamino, C3_6-alkynylamino, carboxy-
C1_3-
alkyiamino or C~7-cycloalkylamino group which may additionally be substituted
in
each case at the amino-nitrogen atom by a C~_5-alkyl, C3_~-cycioalkyl, carboxy-
C~_3-
alkyl, amino-C~_4-alkyl, C~_3-amino-C~_ø-alkyl, 2-[di-(C~_3-alkyl)-amino]-
ethyl, 3-[di-
(C~_3-alkyl)-amino]-propyl, phenyl, pYridYl, pyrrolidinyl, piperidinyl, 2,5-
dihydro-1 H-
pyrrolyl or 1,2,5,6-tetrahydropyridinyl group,
by a pyrroiyl, thienyl, imidazolyi, pyrazolyl, thiazolYl, pyridinyl,
pyrimidinyl, pyrazinyl
~o or pyridazinyl group, optionally substituted by one ~or two C'_3-alkyl
groups, and to
which a phenyl ring may be fused in each case via two adjacent carbon atoms,
or
by a C3_6-cycloaikyleneimino or C3_~-cyciaalkenyleneimino group optionally
substituted by a C~_3-alkyl, carboxy-C~_3-aikyi, hydroxy, hydroxy-C~_3-alkyl,
amino,
~o carboxy, carboxy-C~_3-alkoxy-C~_3-alkyl, carboxy-C~_3-alkylamino-C~_3-alkyl
or
carboxy-C~_3-alkylaminocarbonYl-C~_3-alkyl group, with the proviso that the
hydroxy
and the amino groups are not bound in the 2-position,
R3 denotes a hydrogen, fluorine, chlorine, bromine or iodine atom, a formyl or
2o trifluoromethyl group,
a C'_3-alkoxy, amino, C~_2-alkylamino, di-(C1_2-alkyl)-arnino or C~_2-
afkanoylamino
group,
2s a C~.~-alkyl, C2.~-alkenyl, C~~.-Alkyny( or Cue,.-cycloalkyl group
optionally substituted by
a hydroxy, C~_3-alkoxy, carboxy, carboxy-C1_3-alkoxy oe° CarbOXy-C1_3-
alkylaminocarbonyl group and
R4 denotes a hydrogen, fluorine, chlorine, bromine or iodine atom, a C~_3-
alkyl,
3o trifluoromethy! or C~_3-alkoxy group,
X denotes an oxygen or sulphur atom, a methylene group optionally substituted
by one
or two C~_3-alkyl groups, a carbonyl, suiphinyl, sulphonyl, imino or N-(C~_3-
alkyl)-imino
CA 02445571 2003-10-29
group, a N-(phenyl-C~_3-alkyl)-imino or N-(pyridyl-C~_3-alkyl)-imino group
optionally
substituted by a carboxy group, a N-(C~_3-alkyl)-carbonylimino, N-(carboxy-
C~_3-alkyf)-
imino, C~_3-alkylaminocarbonyl-C1_3-alkylimino, di-(C~_3-alkyl)-aminocarbonyl
or C1-a-
alkylimino group,
R5 denotes a cyano or C~_2-alkyl-cyano group or an amidino group optionally
substituted
by a group which can be cleaved in vivo and
Y1 denotes the group CR'",
Y2 denotes the group CR",
Y3 denotes the group CR'' and
Y~. denotes the group CRZ or
one or two of the groups Y~ to Y4 denotes a nitrogen atom and in each case the
remainder of the groups Y~ to Y~ denote three or two of the groups CR'" to
CRZ, while
2o R'", R", R'' and RZ in each case denote a hydrogen atom or
one or two of the groups RW to RZ independently of one another in each case
denote
a fluorine, chlorine or bromine atom, a straight-chain C~_3-alkyl group, a
hydroxy, C~_3-
alkoxy, amino, C~~-alkylamino or di-(Cs_~-alkyl)-amino group and the remainder
of the
groups RW to RZ in each case represent a hydrogen atom, while
R~ and RZ together may also represent a group of formula
C = N-X'-
NH2
(11).
3o wherein
CA 02445571 2003-10-29
X° is bound in the 4 position relative to the group X in formula (!)
and denotes a
methylene or ethylene group, an oxygen atom, an imino or vinylene group, while
particularly those compounds of general formula (I), wherein
A denotes an ethynylene group, are of exceptional importance,
white the hydrogen atoms in the methyl and methoxy groups mentioned in the
definition
of the above groups or in the methyl moieties contained in the groups of
formula I
~o defined hereinbefore may, unless otherwise stated, be wholly or partially
replaced by
fluorine atoms.
By the abovementioned heteroaryl group is meant a 5-membered heteroaromatic
group, optionally substituted by one or two C~~-alkyl groups, which contains
an imino
group, optionally substituted by a C~_3-alkyl group, an oxygen or sulphur atom
or an
imino group optionally substituted by a C~_3-alkyl group, an oxygen or sulphur
atom and
one or two nitrogen atoms as well as the partially hydrogenated derivatives
thereof,
particularly the dihydro derivatives thereof, or a 6-membered heteroaromatic
group
which contains one, two or three nitrogen atoms, while additionally a phenyl
ring may
2o be fused to the abovementioned 5- and 8-membered heteroaromatic rings via
two
adjacent carbon atoms.
Moreover, the compounds according to the invention may be in the form of
prodrugs.
For example, the carboxy groups mentioned above in the definitions may be
replaced
2~ by a tetrazolyl group or by a group which may be converted into a carboxy
group in
vivo, e.g. by a hydroxymethyl or formyi group, by a carboxy group esterified
with an
alcohol wherein the alcoholic moiety is preferably a C~.~-alkanol, a phenyl-
C~_3-alkanol,
a C3_9-cycloaikanol, white a C~_$-cycloalkanol may additionally be substituted
by one or
two C~_3-alkyl groups, a C~_$-cycloalkanoi wherein a methylene group is
replaced in the
ao 3- or 4-position by an oxygen atom or by an imino group optionally
substituted by a C~_3
alkyl, phenyl-C~_3-alkyl, phenyl-C~_3-alkoxycarbonyl or C2_6-alkoxycarbonyl or
C2~
alkanoyf group and the cycloalkanol moiety may additionally be substituted by
one or
two C1_3-alkyl groups, a C4_7-cycloalkenol, a C3_5-alkenol, a phenyl-C3_5-
alkenol, a C3_5-
CA 02445571 2003-10-29
-7-
alkynol or phenyl-C3_5-alkynol, with the proviso that no bond to the oxygen
atom starts
from a carbon atom that carries a double or triple bond, a C3_$-cycloafkyl-
G1_3-afkanol, a
bicycloafkanol with a total of 8 to 10 carbon atoms which is additionally
substituted in
the bicycloalkyl moiety by one or two C~_~-alkyl groups, a 1,3-dihydro-oxo-
1-isobenzofuranol or an alcohol of formula
RaCO-O-(RbCRC)-OH, wherein
Ra denotes a C1_$-alkyl, C5_7-cycloalkyl, phenyl or phenyl-C~_3-alkyl group,
Rb denotes a hydrogen atom, a C~_3-alkyl, C5_7-cycloalkyl or phenyl group and
R~ denotes a hydrogen atom or a C~_3-alkyl group,
and the imino or amino groups mentioned in the definition of the groups may be
substituted by a group which can be cleaved in vivo, e.g. by a hydroxy- C~_8-
alkoxy,
allyloxy, phenyloxy, benzylvxy, 3-methoxybenzyloxy, 4-methylbenzyloxy or 4-
chlorophenyl-C~_6-alkyloxy group, by an acyl group such as the benzoyl or
pyridinoyl
group or a C~_~6-alkanoyl group such as the formyf, acetyl, propionyf,
butanoyf,
2o pentanoyl or hexanoyl group, by an alfyloxycarbonyl group, by a C~_»-
alkoxycarbonyl
group such as the methyloxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl,
isopropyloxycarbonyf, butyloxycarbonyf, tert.butyloxycarbonyl,
pentyloxycarbonyl,
hexyioxycarbonyl, octyloxycarbonyl, nonyfoXycarbonyl, decyloxycarbonyl,
undecyloxycarbonyl, dodecyfoxycarbonyl or hexadecyloxycarbonyl group, by a
phenyl-
C~_~6-afkoxycarbonyl group such as the benzyloxycarbonyi,
phenylethyloxycarbonyl or
phenylpropyloxycarbonyl group, by a C~_3-afkylsulphonyl-C2~-alkoxycarbonyf,
C~_3'
alkoxy-C2~-alkoxy-C2~-alkoxycarbonyi or RaCO-O°tRbCR~)-O-CO- group
wherein Ra to
Rb are as hereinbefore defined.
3o Moreover, the saturated alkyl and alkoxy moieties containing more than 2
carbon atoms
mentioned in the definitions above as well as the alkanoyl and unsaturated
alkyl
moieties which contain more than 3 carbon atoms also include the branched
isomers
thereof such as the isopropyl, tert.butyf, isobutyl group, etc.
CA 02445571 2003-10-29
_$_
Preferred compounds of general formula B of the present invention are those
wherein
A denotes an ethynylene or an ethylene group,
s
n denotes one of the numbers 0 or 1,
R~ denotes a hydrogen atom, a C~_3-alkyl, phenyl, pyridyl or carboxy-C~_~-
alkyl group,
1o Ar denotes a phenyl or pyridyl group substituted by the groups R2 to R4,
while
R2 denotes a C~_6-alkyl group which may be substituted by a carboxy, amino,
C~.3-
alkylamino, carboxy-C,_3-alkylamino, di-(C,._3-alkyl)-amino, N-(carboxy-C,_3-
alkyl)-C~_3-
alkylamino or C3_~-cycloalkylamino group,
~s
a phenyl, pyridyl or pyrimidyf group which may be sut~stituted by a fluorine,
chlorine
or bromine atom, by a C~_3-alkyl, carboxy-C~_~-alkyl, C1_3-alkoxy,
aminosulphonyl,
C~_3-alkylsulphonyl or C~_3-alkylaminosulphonyl group,
2o a C1_5-alkylamino, carboxy-C1_3-alkylamino, di-(C~_~-aNkyl}-amino, N-
(carboxy-C~~-
alkyl)-C~_5-alkylamino, C3_~-cycloalkylamino or N-(carksoxy-C~-3-alkyl)-C3_7-
cycloalkylamino group,
a C3_5-cycloalkylcarbonylamino, N-(C~_3-alkyl)-C~~.-alkylcarbonylamino or N-
(C~_3-
25 alkyl)-C3_~-cycloalkylcarbonylamino group, while
the abovementioned N-(C~_3-alkyl) moieties may additionally be substituted by
a
carboxy group,
3o a 5- to 7-membered cycloalkyfeneimino group,
CA 02445571 2003-10-29
_g_
an amino, C~_5-aikylamino or C3_~-cycloalkylamino group which is substituted
in each
case at the amino-nitrogen atom by a C~_3-alkylcarbonyl or carboxy-C~_~-
alkylcarbonyl
group, while additionally
the alkyl moiety of the abovementioned C1_5-alkylcarbonyB- and carboxy-C1_3-
alkylcarbonyl group may be substituted by an amino, hydroxy, carboxy-C~_3-
alkoxy,
carboxy-C~~-alkyiaminocarbonyl, carboxy-C1_3-alkylamino, N-(C~_3-alkyl)-
carboxy-
C~-3-alkyiamino or amino-C~_3-alkyicarbonylamino group,
1o a carbonyl group which is substituted
by a C~~.-alkyl or C3_5-cycloaikyl group,
by a phenyl group,
by an amino, C~_5-aikylamino, C2_5-alkenyiamirio, C3_6-aikynylamino, carboxy-
C~_3-
alkylamino or C3_,-cycloalkyfamino group which may additionally be substituted
in
each case at the amino-nitrogen atom by a C~_5-alkyl group, or
2o by a C3_6-cycloalkyleneimino or C3.6-cycloalkenylen~eimino group optionally
substituted by a C~_3-alkyl, carboxy-C~~-alkyl, hydroxy, hydroxy-C~_3-alkyl,
amino or
carboxy group, with the proviso that the hydroxy and the amino groups are not
bound in the 2-position,
R3 denotes a hydrogen, fluorine, chlorine or bromine atom or a triftuoromethyl
group,
a C~_3-alkoxy, amino, C~_2-aikylamino, di-(C~_ralkyl)-amino or C~_2-
alkanoylamino
group,
so a C1_4-alkyl, C2~.-alkynyl or C3~-cycloalkyl group and
R4. denotes a hydrogen atom or a C~_3-alkyl group,
CA 02445571 2003-10-29
°
(
X denotes an oxygen atom, an imino, N-(C~_~-alkyl}-imino group, a N-benzyl-
imino or N-
(pyridyl-C~_3-alkyl)-imino group optionally substituted by a carboxy group, a
N-(C'_3-
alkyl)-carbonylimino or N-(carboxy-C~_3-alkyl)-imino group,
R5 denotes a cyano group or an aminomethyl or amidino group optionally
substituted by
a group which can be cleaved in vivo and
Y~ denotes the group CRW,
~o Y2 denotes the group CR",
Y3 denotes the group CRy and
Y.~ denotes the group CRZ or
one of the groups Y~ to Y~ denotes a nitrogen atom and the remainder of the
groups Y~
to Y4 represent three of the groups CR'" to CRZ, white
RW, RX, R'' and RZ in each case denote a hydrogen atom or
one of the groups Rw to RZ denotes a chlorine atom, a C,_3-alkyl group, a
hydroxy,
C,_3-alkoxy, amino or G~_3-alkylam~n0 group and the remainder of the groups Rw
to RZ
in each case represent a hydrogen atom, while
particularly those compounds of general formula (I), wherein
A denotes the ethynylene group, are of exceptional importance,
while the hydrogen atoms in the methyl and methoxy groups mentioned in the
definition
of the above groups or in the methyl moieties contained in the groups of
formula i
defined hereinbefore may, unless otherwise stated, be wholly or partially
replaced by
fluorine atoms,
CA 02445571 2003-10-29
the prodrugs, the tautomers, the stereoisomers, the mixtures thereof and the
salts
thereof.
Particularly preferred compounds of the present invention are the compounds of
general formula la
R Rs
3
R2 ~ A'.'_'(CI"'12)~ (CI~'°IR1~X
R4 -NH
H2N
9 (la)
wherein
1o A denotes an ethylene or ethynylene group,
n denotes one of the numbers p or 1,
R~ denotes a hydrogen atom, a C~_3-alkyl, phenyl or carboxy-C~_3-alkyl group,
R2 denotes a phenyl group which may be substituted by an aminosulphonyl, C~_3-
alkylsulphonyl or C~_3-alkylaminosulphonyi group,
a di-(C~_5-alkyl)-amino, N-(carboxy-C~_3-alkyl)-C,_5-alkylamino or N-(carboxy-
C~_3-alkyl)-
2o C3_~-cycloalkylamino group,
a N-(C~_3-alkyl)-C~~.-alkylcarbonylamino or N-(C~_~-alkyl)-t~3_5-
cycloalkylcarbonylamino
group,
2s a C~_5-alky(amino or C~~-cycloalkylamino group which is substituted in each
case at the
amino-nitrogen atom by a C~_3-aikylcarbonyl or carboxy-G~_3-alkylcarbonyl
group,
a carbonyl group which is substituted
CA 02445571 2003-10-29
ti -1a-
by a C~_~-alkyl or C3_7-cycloalkyl group,
by a phenyl group,
by a C~_5-alkylamino, C2_5-alkenylamino, C~_6-alkynylamino or C3_7-
cycloafkylamino
group which may additionally be substituted in each case at the amino-nitrogen
atom
by a C~_5-alkyl group, or
~o by a pyrrolidino or 2,5-dihydro-1 H-pyrrolyl group optionally substituted
by a C~_3-alkyl,
carboxy-C~_3-alkyl, hydroxy, hydroxy-C~_3-alkyl, amino or carboxy group, with
the
proviso that the hydroxy and amino groups are not bound in the 2-position,
R3 denotes a hydrogen, fluorine, chlorine or bromine atom or a trifluoromethyl
group,
a C~_3-alkoxy or a C~~-alley! group and
R4 denotes a hydrogen atom or a C~_3-alkyl group,
2o X denotes an oxygen atom, an imino, N-(C~_3-alkyl)-imino, N-benzyl-imino, N-
(C~_3-
alkyl)-carbonylimino or N-(carboxy-C~_3-alkyl)-imino group,
R5 denotes a cyano group or an aminomethyl or amidino group optionally
substituted by
a group which can be cleaved in vivo and
2s
R6 denotes a chlorine atom or a C~_3-alkyl, hydroxy, C1_3-alkoxy, amino or
C1_3-
alkylamino group, while
particularly those compounds of general formula (l), wherein
A denotes the ethynylene group, are of exceptional importance,
CA 02445571 2003-10-29
-13-
while the hydrogen atoms in the methyl and methoxy groups mentioned in the
definition
of the above groups or in the methyl moieties contained in the groups of
formula I
defined hereinbefore may, unless otherwise stated, be wholly or partially
replaced by
fluorine atoms,
the prodrugs, the tautomers, the stereoisomers, the mixtures thereof and the
salts
thereof.
The following may be mentioned as examples of particularly preferred
compounds:
(1 ) 3-{3-[4-(N-acetyl-cyclopentylamino)-3-methyl-phenyl]-propargylamino}-
benzamidine,
{2) 4-hydroxy-3-{3-[4-(pyrrolidin-1-yl-carbonyl)-3-methyl-phenyl]-
propargylamino}-
benzamidine,
(3) 3-{3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl}-phenyl]-propargylamino~-
benzamidine,
(4) 3-{N-methyl-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-phenyl]-
propargylarnino}-
2o benzamidine,
(5) 3-{N-acetyl-3-[3-methyl-4-(pyrrofidin-1-yl-carbonyl}-phenyl]-
propargylamino}-
benzamidine,
(6) 3-{4-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-phenyl]-but-~-inylamino}-
benzamidine,
(7) 3-{3-[3-methyl-4-{pyrrolidin-1-yl-carbonyl}-phenyl]-propyl-amino}-
benzamidine,
(8} 3-{3-[2,5-dimethyl-4-(pyrrolidin-1-yl-carbonyl)-phenyl]-propargylamino}-
ao benzamidine,
(9) 3-[3-(2'-aminosulphonyl-biphenyl-~-yl)-propargyfamino]-benzamidine,
CA 02445571 2003-10-29
-14-
(10) 3-{3-[3-methyl-4.-(pyrrolidin-1-yl-carbonyl)-phenyl]-propargyl-oxy)-
benzamidine,
(11) 3-{1-methyl-3-[3-methyl-4-(pyrroiidin-1-yl-carbonyl)-phenyl]-
propargylarnino}-
benzamidine,
(12) 3-{N-ethoxycarbonylmethyl-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-
phenylj-
propargylamino}-benzamidine,
(13) 3-{N-methyl-3-[4-(N-acetyl-cyciopentylamino)-3-methyl-phenyiJ-
propargylamino}-
~o benzamidine,
414) 3-{N-hydroxycarbonylmethyl-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-
phenyl]-
propargylamino}-benzamidine,
~5 (15) 3-{N-methyl-3-{4-[N-(3-ethoxycarbonyl-propionyP)-cyclopentylamino]-8-
methyl-
phenyl)-propargylamino}-benzamidine,
(1fi) 3-{N-methyl-3-{4-[N-(2-ethoxycarbonyl-acetyl)-cyclopentylaminoj-3-methyl-
phenyl}-
propargylamino}-benzamidine,
(17) 3-{N-methyl-3-{4-[N-(2-hydroxycarbonyl-acetyl)-cyclopentylamino]-3-methyl-
phenyl}-propargylamino)-benzamidine,
(18) 3-{3-[4-(pyrroiidin-1-yl-carbonyl)-phenyl]-propargylamino)-benzamidine,
(19) 3-{N-methyl-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-phenyl]-propyl-
amino)-
benzamidine,
(20) 3-{N-methyl-3-[3-methyl-4-(2,5-dihydropyrrol-1-yl-carbonyl)-phenyl]-
so propargylamino}-benzamidine,
(21) 3-{3-[3-methyl-4-(2,5-dihydropyrrol-1-yl-carbonyl)-phenyl]-
propargylarnino}-
benzamidine,
CA 02445571 2003-10-29
_15_
(22) 3-[N-methyl-3-(4-isopropylcarbonyi-3-methyl-phenyl)-propargyiamino]-
benzamidine,
(23) 3-{N-benzyf-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-phenyl]-
propargylamino}-
benzamidine,
(24) 3-{N-methyl-3-[3-methyl-4-(N-methyl-propargylamino-carbonyl)-phenyl]-
propargylamino}-benzamidine,
~o
(25) 3-{N-methyl-3-[4-(N-allyi-methyiamino-carbonyl)-;3-methyl-phenyl]-
propargyfamino}-benzamidine,
(26) 3-{N-methyl-3-[4-(N-ethyl-methyfamino-carbonyl)-3-methyl-phenyl]-
propargylamino}-benzamidine,
(27) 3-{N-methyl-3-[4-(N-isopropyl-methylamino-carbonyl)-3-methyl-phenyl]-
propargylamino}-benzamidine,
20 (28) 3-{N-methyl-3-[2'-aminosulphonyi-biphenyl-4-yl]-propargylamino}-
benzamidine,
(29) 3-[N-methyl-3-(4-diethylaminocarbonyl-3-methyl-phenyl)-propargylamino]-
benzamidine,
2~ (30) 3-{N-(2-ethoxycarbonylethyl)-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-
phenyl]-
propargylamino}-benzamidine,
(31 ) 3-{N-(2-ethoxycarbonylethyl)-3-[3-methyl-4-(2,5-dihydropyrrol-1-yl-
carbonyl)-
phenyl]-propargylamino}-benzamidine,
(32) 3-{N-(4-ethoxycarbonylphenylmethyl)-3-[3-methyl-~>~-(pyrrolidin-1-yl-
carbonyi)-
phenyl]-propargylamino]-benzamidine,
CA 02445571 2003-10-29
_16_
(33) 3-{N-(3-methoxycarbonylphenylmethyl)-3-[3-methyl-4-(pyrrolidin-1-yl-
carbonyl)-
phenyl]-propargylamino}-benzamidine,
(34) 3-{N-(4-hydroxycarbonylphenylmethyl}-3-[3-methyl-4-(pyrrolidin-1-yl-
carbonyl}-
phenyl]-propargyiamino}-benzamidine,
(35) 3-{N-(3-hydroxycarbonylphenylmethyl)-3-[3-methyl-4-(pyrrolidin-1-yl-
carbonyl)-
phenyl]-propargylamino)-benzamidine,
(36) 3-{N-(2-hydroxycarbonylethyl)-3-[3-methyl-4-(pyrr~olidin-1-yl-carbonyl)-
phenyl]-
propargylamino}-benzamidine,
(37} 3-{N-benzyl-3-[3-methyl-4-(2,5-dihydropyrrol-1-yl-carbonyl}-phenyl]-
propargylamino}-benzamidine,
(38) 3-[N-benzyl-3-(4-isobutyryl-3-methyl-phenyl}-propargylamino]-benzamidine,
(39} 3-[N-benzyl-3-(4-benzoyl-3-methyl-phenyl)-propargylamino]-benzamidine,
(40) 3-{N-benzyl-3-[2'-aminosulphonyl-biphenyl-4-yl]-propargylamino}-
benzamidine,
(41 ) 3-{N-benzyl-3-[2'-aminosulphonyl-biphenyl-4-yl]-propylamino}-
benzamidine,
(42} 3-{N-(pyridin-2-ylmethyl)-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl~phenyl]-
propargyiamino}-benzamidine,
(43) 3-{N-(pyridin-3-yimethyl)-3-[3-methyl-4-(pyrroiidin-1-yl-carbonyl)-
phenyl]-
propargyiamino}-benzamidine,
so (44) 3-[N-(2-ethoxycarbonylethyl)-3-(4-cyclopentylcarbonyl-3-methylphenyl)-
propargyiamino]-benzamidine and
CA 02445571 2003-10-29
' -17-
(45) 3-[N-(4-ethoxycarbonylphenylmethyl)-~-{2'-aminosulphonylbiphenyl-4-yl]-
propargyiamino]-benzamidine
and the salts thereof.
According to the invention the compounds of general formula I are obtained by
known
methods, for example by the following methods:
a) Reacting a compound of general formula
Ar - Z~ , (I II)
wherein
Ar is as hereinbefore defined and
Z1 denotes a leaving group such as a halogen atom or a sulphonyloxy group,
e.g. a
chlorine, bromine or iodine atom or a trifluoromethylsulphonyloxy group, with
a
compound of general formula
Y2 Y3,
H--A'-(CFi2)~ CFiR~-X---~~ ~Y4
Y
{l~~)
wherein
2s R~, n, Y~, Y2, Y3, Y4 and X are as hereinbefore defined,
R5' has the meanings given for R~ hereinbefore, with the proviso that any
amino or
imino group present is protected by a conventional protecting group, and
CA 02445571 2003-10-29
-18-
A' denotes an ethynyl group, or
b) reacting a compound of general formula
Ar - Z~ , (I I ()
wherein
Ar is as hereinbefore defined and
Z1 denotes a leaving group such as a halogen atom or c~ sulphonyloxy group,
e.g. a
chlorine, bromine or iodine atom or a trifluoromethylsulphonyloxy group, with
a
compound of general formula
H A~'_(CI'/2)n C.~HR1 ~H
, (11/)
wherein n and R~ are as hereinbefore defined and A' denotes an ethynylene
group, the
reaction product is reacted with 1-bromoprop-2-ene and the resulting compound
of
formula
Ar-A°(CH2)~-CHR'-Br ' (V)
is reacted with a compound of general formula
Y2 Y3
H2N~~ ,Y4
R5 , (1e/)
wherein
CA 02445571 2003-10-29
_19_
Y~, Y2, Y3 and Y4 are as hereinbefore defined and Rs' has the meanings given
for R5
hereinbefore, with the proviso that any amino or imino group present is
protected by a
conventional protecting group,
optionally followed by catalytic hydrogenation and/or cleaving of any
protecting group
used.
The reaction of an ethynyl compound according to formula 111 is preferably
carried out in
a solvent such as acetonitrile, diethyl ether, tetrahydrofuran or
dimethylformamide in the
~o presence of a palladium catalyst such as bis(triphenylptaosphine)-
palladium(ll)chloride
or tetrakis-(triphenylphosphine)-palladium(0) in the presence of a tertiary or
inorganic
base such as triethylamine, N-isopropyl-diethylamine, potassium tert.
butoxide, sodium
carbonate or caesium carbonate and in the presence of a reaction accelerator
such as
a copper halide such as copper(1) iodide and at temperatures between 20 and
120°C,
preferably at temperatures between 40 and 100°C, (cf. also K.
Sonogashira,
Comprehensive Organic Synthesis, Vol. 3, page 52ff., Pergamon Press, Oxford
1991 ).
The protecting groups optionally used and their removal are described
hereinafter (cf.
also T. Greene, Protective Groups in Organic Synthesis, Wiley lnterscience,
New York
20 1981 ).
c) To prepare a compound of general formula l wherein the Ar-A group contains
a
carboxy group and R5 is as hereinbefore defined or the Ar-A group is as
hereinbefore
defined and R~ denotes an amino, amen~-C~_3-alkyl or amidino group or the Ar-A
group
2s contains a carboxy group and R5 denotes an amino, amino-C~_3-alkyl or
amidino group:
Converting a compound of general formula
Y2 Y3
Ar'-A-(CH2)r, CHR~-X--~~ ~Ya
Y
R5
CA 02445571 2003-10-29
-~o-
wherein
A, n, R~, Y~, Y2, Y3, Y~ and X are as hereinbefore defined,
Ar' and R5" have the meanings given for Ar and R5 hereinbefore with the
proviso that
Ar° contains a group which can be converted into a carboxy group by
hydrolysis,
treatment with an acid or base, thermolysis or hydrogenolysis and R5' has the
1o meanings given for R5 hereinbefore or
Ar' has the meanings given for Ar hereinbefore and R5''' denotes a group which
can be
converted into an amino, amino-C1_3-alkyl or amidino group by hydrolysis,
treatment
with an acid or base, thermolysis or hydrogenolysis or
Ar' contains a group which can be converted into a carboxy group by
hydrolysis,
treatment with an acid or base, thermolysis or hydrogenolysis and R5" contains
a group
which can be converted into an amino, amino-C~.3-alkyl or amidino group by
hydrolysis,
treatment with an acid or base, thermolysis or hydrogenolysis,
by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis
into a
compound of general formula i wherein the Ar-A group contains a carboxy group
and
R~ is as hereinbefore defined or the Ar-A group is as hereinbefore defined and
R5
denotes an amino, amino-C~.3-alkyl or amidino group or the Ar-A group contains
a
carboxy group and R~ denotes an amino, amino-C~_3-alkyl or amidino group.
By a group which may be converted into a carboxy group is meant for example a
carboxyl group protected by a protecting group, such as the functional
derivatives
thereof, e.g. the unsubstituted or substituted amides, esters, thioesters,
so trimethylsiiylesters, orthoesters or iminoesters thereof, which may
conveniently be
converted into a carboxyl group by hydrolysis,
CA 02445571 2003-10-29
-21
the esters thereof with tertiary alcohols, e.g. the tart. butyl ester thereof,
which may
conveniently be converted into a carboxyl group by treatment with an acid or
thermolysis, and
the esters thereof with arylalcohois, e.g. the benzyl esters thereof, which
may
conveniently be converted into a carboxyl group by hydrogenolysis.
The hydrolysis is conveniently carried out either in the presence of an acid
such as
hydrochloric acid, sulphuric acid, phosphoric acid, acetic acid,
trichloroacetic acid,
1o trifluoroacetic acid or mixtures thereof or in the presence of a base such
as lithium
hydroxide, sodium hydroxide or potassium hydroxide in a suitable solvent such
as
water, water/methanol, waterlethanol, waterlisopropanol, methanol, ethanol,
water/-
tetrahydrofuran or water/dioxane at temperatures between -10 and 120°C,
e.g. at
temperatures between ambient temperature and the boiling temperature of the
reaction
mixture.
if a compound of general formula V contains the tert.butyi or
tert.butyloxycarbonyf
group for example, these may also optionally be cleaved by treatment with an
acid such
as trifluoracetic acid, formic acid, p-toluenesulphonic acid, sulphuric acid,
hydrochloric
2o acid, phosphoric acid or polyphosphoric acid, optionally in an inert
solvent such as
methylene chloride, chloroform, benzene, toluene, diethyl ether,
fietrahydrofuran or
dioxane, preferably at temperatures between -10 and 12 0°C, e.g. at
temperatures
between 0 and 60°C, or also thermally, optionally in an inert solvent
such as methylene
chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxane and
preferably in the
presence of a catalytic amount of an acid such as p-toluenesulphonic acid,
sulphuric
acid, phosphoric acid or polyphosphoric acid, preferably at the boiling
temperature of
the solvent used, e.g. at temperatures between 40 and 120°C.
If a compound of general formula V contains the benzyloxy or benzyloxycarbonyl
group
3o for example, these may also be cleaved by hydrogenolysis in the presence of
a
hydrogenation catalyst such as palladiumlcharcoal in a suitable solvent such
as
methanol, ethanol, ethanol/water, glacial acetic acid, ethyl acetate, dioxane
or
CA 02445571 2003-10-29
-~2-
dimethylformamide preferably at temperatures between 0 and 50°C, e.g.
at ambient
temperature, and a hydrogen pressure of 1 to 5 bar.
d) to prepare a compound of genera! formula 1 wherein R5 denotes an amidino
group:
Reacting a compound of general formula
Y2 Y~
Ar-A--(CH2)n CI-1R~ X--~~ ~Y4
Y
, (~l)
optionally formed in the reaction mixture,
wherein
A, Ar, n, R~, Y~, Y2, Y3, Y4 and X are as hereinbefore defined and
R5' denotes one of the groups mentioned for R5 hereinbefore, with the proviso
that R5"
denotes a Z~-(HN=)C- group, wherein
Z1 denotes an alkoxy or aryfalkoxy group such as the methoxy, ethoxy, n-
propoxy,
2o isopropoxy or benzyloxy group or an alkylthio or arylalkyithio group such
as the
methylthio, ethylthio, n-propylthio or benzylthio group,
with an ammonium salt such as diamrnonium carbonate or ammonium acetate.
The reaction is expediently carried out in a solvent such as methanol,
ethanol,
n-propanol, tetrahydrofuran or dioxane at temperatures between 0 and
150°C,
preferably at temperatures between 0 and 80°C.
A compound of general formula dJl is obtained, for example, by reacting a
3o corresponding cyano compound with a corresponding alcohol such as methanol,
CA 02445571 2003-10-29
-~3-
ethanol, n-propanol, isopropanol or benzylaicohol in the presence of an acid
such as
hydrochloric acid or by reacting a corresponding amide with a trialkyloxoniurn
salt such
as triethyloxonium tetrafluoroborate in a solvent such as methy(ene chloride,
tetrahydrofuran or dioxane at temperatures between 0 and 50°C, but
preferably at
20°C, or a corresponding nitrite with hydrogen sulphide, conveniently
in a solvent such
as pyridine or dimethylformamide and in the presence of a base such as
triethylamine,
and subsequent alkylation of the thioamide formed with a corresponding alkyl
or
alkylaryl halide.
1o e) to prepare a compound of general formula 1 wherein R~ denotes an amidino
group
which is substituted by a hydroxy or C~_8-alkoxy group:
Reacting a compound of general formula
Y2 Y~
Ar-A-(CH2)n CHR~-X~~ Ya.
Y
~5, , (~/I)
optionally formed in the reaction mixture
wherein
A, Ar, n, Y~, Y2, Y3, Y4, R~ and X are as hereinbefore defined and
R~" denotes one of the groups mentioned for R~ hereinbefore, with the proviso
that R~
denotes a Z1-(HN=)C- group, wherein
Z~ denotes an a(koxy or aryla(koxy group such as the methoxy, ethoxy, n-
propoxy,
isopropoxy or benzyloxy group or an alkylthio or aralky(thio group such as the
methylthio, ethylthio, n-propylthio or benzylthio group,
CA 02445571 2003-10-29
-24-
with hydroxylamine, C~_$-alkyloxylamine, allyloxylamine, phenyloxylamine,
benzyloxylamine, 3-methoxybenzyloxylamine, 4-methylbenzyloxylamine, 4-
chlorophenyl-C~_6-alkyloxylamines or the salts thereof.
The reaction is expediently carried out in a solvent such as methanol,
ethanol,
n-propanol, water, methanol/water, tetrahydrofuran, tetrahydrofuranlwater,
dioxane or
dioxanelwater in the presence of a base such as triethylamine at temperatures
between
0 and 150°C, preferably at temperatures between 0 and 80°C.
1o f) to prepare a compound of general formula l wherein X denotes an oxygen
or sulphur
atom, a carbonyl, imino or N-(C1_3-alkyl)-imino group:
Reacting a compound of general formula
~5 Ar - A - {CH2)" - CHR~ - Z2 , {VII)
wherein
A, Ar, n and R~ are as hereinbefore defined and
Z2 denotes a leaving group such as a halogen atom or a sulphonyloxy group,
e.g. a
bromine or iodine atom, a methanesulphonyloxy, trifluoromethanesulphonyloxy or
p-toluenesulphonyloxy group, with a compound of general formula
Y2 Y~
U ! Y~
Y~
R5 , {Vill)
wherein
Y1, Y2, Y3, Y~ and R~ are as hereinbefore defined and
CA 02445571 2003-10-29
-2b-
U denotes a hydroxy, mercapto, amino, N-phenyl-(C~.3, alkyl)-amino, N-pyridyl-
(C~_3-
alkyl)-amino, N-(C~_3-alkyl)-amino or C~_3-alkylcarbonyl-amino group.
The reaction is preferably carried out in a solvent such as methanol, ethanol,
methylene
s chloride, tetrahydrofuran, toluene, dioxane, dimethyisulphoxide or
dimethylformamide,
optionally in the presence of an inorganic or a tertiary organic base,
preferably at
temperatures between 20°C and the boiling temperature of the solvent
used.
g) to prepare a compound of general formula I wherein Ar and/or Y contains) a
group
~o which can be cleaved in vivo:
Reacting a compound of general formula
Yz Y~
Ar"-A'(Ci°i~)n CHR1-~C--~~
Y
R5" , (iX)
15 wherein
A, n, RR, Y~, Y2, Y3, Y4 and X are as hereinbefore defined,
Ar°' and R~"' have the meanings given for Ar and R5 hereinbefore, with
the proviso that
Ar" contains a carboxy group and R~"° has the meanings given for R5
hereinbefore or
Ar" has the meanings given for Ar hereinbefore and R5 " contains an amino,
amino-C~_3-
alkyl or amidino group or
Ar" contains a carboxy group and R5"' contains a group which may be converted
into an
amino, amino-C~_3-alkyl or amidino group, with a compound of general formula
Z3 ° R7 a (X)
CA 02445571 2003-10-29
-26-
wherein
R7 denotes a C~_$-alkoxycarbonyl group, a RFC~-O-(Rt,CR~)- group or the aryl
group of
one of the groups mentioned hereinbefore which may be cleaved m vivo, where Ra
to
R~ are as hereinbefore defined, and
Z3 denotes a nucleofugic leaving group such as a halogen atom, e.g. a
chlorine,
bromine or iodine atom, or a p-nitrophenyl group or also, if Ar" contains a
carboxy
group, Z3 denotes a hydroxy group.
1o 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 acid activating agent or a
dehydrating agent and optionally in the presence of an inorganic or a tertiary
organic
base, preferably at temperatures between 20°C and the boiling
temperature of the
solvent used.
With a compound of general formula X wherein Z3 denotes a nucleofugic leaving
group,
the reaction is preferably carried out in a solvent such as methylene
chloride,
acetonitrile, tetrahydrofuran, toluene, dimethylformamide or
dimethylsulphoxide,
optionally in the presence of a base such as sodium hydrides potassium
carbonate,
potassium tert. butoxide or N-ethyl-diisopropylamine at temperatures between 0
and
60°C.
With a compound of general formula X wherein Z3 denotes a hydroxy group, the
reaction is optionally carried out in a solvent or mixture of solvents such as
methylene
chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran,
benzeneltetrahydrofuran or dioxane in the presence of a dehydrating agent,
e.g. in the
presence of isobutyl chlorofarmate, tetraethyl orthocarbonate, trimethy!
orthoacetate,
2,2-dimethoxypropane; tetramethoxysilane, thionyi chloride,
trimethylchlorosilane,
3o phosphorus trichloride, phosphorus pentoxide, N,N'-
dicyclohexylcarbodiimide,
N,N'-dicyclohexylcarbodiimidelN-hydroxysuccinimide, N,N°-
dicyclohexylcarbodiimide/1-
hydroxybenzotriazole, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluranium
tetrafiuoroborate, 2-(1H-benzotriazoi-1-yl)-1,1,3,3-tetramethyluronium
CA 02445571 2003-10-29
tetrafluoroboratel1-hydroxybenzotriazole, N,N°-carbonyldiimidazole or
triphenylphosphine/carbon tetrachloride, and optionally with the addition of a
base such
as pyridine, 4-dirnethylaminopyridine, N-methylmorphoiine or triethylamine,
conveniently at temperatures between 0 and 150°C, preferably at
temperatures
between 0 and 100°C.
If in a compound of general formula X the group Z3 denotes a hydroxy group,
the
reaction may also be carried out with one of the reactive derivatives thereof
such as the
esters, imidazolides or halides thereof, preferably in a solvent such as
methylene
~o chloride or ether and preferably in the presence of a tertiary organic base
such as
triethylamine, N-ethyldiisopropylamine or N-methyfmorpholine, at temperatures
between 0 and 150°C, preferably at temperatures between 50 and
100°C.
If according to the invention a compound of general formula l is obtained
wherein R5
~5 denates an amidino group, this may be converted by alkylation with a
haloacetic acid
derivative, by subsequent hydrolysis and decarboxylation into a corresponding
amidino
compound substituted by one or two methyl groups andJor
if a compound of general formula l is obtained wherein F~~ denotes a
hydroxyamidino
2o group, this may be converted by catalytic hydrogenation into a
corresponding amidino
compound andlor
if a compound of general formula I is obtained which contains a double or
triple bond,
this may be converted by catalytic hydrogenation into a corresponding
saturated
25 compound and/or
if a compound of general formula i is obtained wherein X denotes a sulphur
atom, this
may be converted by Oxidation into a corresponding suiphinyl or suiphonyl
compound
andlor
if a compound of general formula I is obtained which contains a carboxy group,
this
may be converted by means of a corresponding amine into a corresponding amide.
CA 02445571 2003-10-29
-28-
The subsequent alkylation is conveniently carried out in a solvent such as
methylene
chloride, tetrahydrofuran, dioxane, 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-
ethyldiisopropylamine
or N-methylmorpholine, which may simultaneously also serve as solvent, 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.
~o The subsequent hydrolysis is conveniently carried out either in the
presence of an acid
such as hydrochloric acid, sulphuric acid, phosphoric acid, acetic acid,
trichloroacetic
acid, trifiluoroacetic acid or mixtures thereof or in the presence of a base
such as lithium
hydroxide, sodium hydroxide or potassium hydroxide in a suitable solvent such
as
water, water/methanoi, water/ethanol, waterlisopropanol, methanol, ethanol,
1s waterltetrahydrofuran or waterldioxane.
The subsequent decarboxylation is carried out in the presence of an acid as
hereinbefore described at temperatures between -10 and 120°C, e.g. at
temperatures
between ambient temperature and the boiling temperature of the reaction
mixture.
The subsequent catalytic hydrogenation is preferably carried out in the
presence of a
hydrogenation catalyst such as paliadium/charcoal and in a suitable solvent
such as
methanol, ethanol, ethanoUwater, glacial acetic acid, ethyl acetate, dioxane
or
dimethylformamide preferably at temperatures between 0 and 50°C, e.g.
at ambient
2s temperature, and at a hydrogen pressure of 1 to 5 bar.
The subsequent oxidation is preferably carried out in a solvent or mixture of
solvents,
e.g. in water, water/pyridine, acetone, methylene chloride, acetic acid,
acetic acidlacetic
anhydride, dilute sulphuric acid or trifluoracetic acid, conveniently at
temperatures
3o between -80 and 100°C, depending on the oxidising agent used.
To prepare a corresponding suiphinyl compound of general formula I the
oxidation is
conveniently carried out with one equivalent of the oxidation agent used, e.g.
with
CA 02445571 2003-10-29
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
triffuoracetic 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, with chromic acid in glacial acetic acid or
in acetone at 0 to
20°C and with sulphuryl chloride in methylene chloride at -70°C,
and the resulting
thioether-chlorine complex is conveniently hydrolysed with aqueous ethanol.
To prepare a sulphonyl compound of general formula l, the oxidation is carried
out
starting from the 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 acidlacetic anhydride, trifluoracetic
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 m-chloroperbenzoic acid in glacial acetic acid, trifluoroacetic acid,
methylene
2o 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, sodium periodate or
potassium
permanganate in acetic acid, waterlsulphuric acid or in acetone at 0 to
20°C.
The subsequent amide formation is preferably carried out in a solvent or
mixture of
2s solvents such as methylene chloride, dimethylformamide, benzene, toluene,
chlorobenzene, tetrahydrofuran, benzeneltetrahydrofuran or dioxane in the
presence of
a dehydrating agent, e.g. in the presence of isobutyl chloroformate,
tetraethyl
orthocarbonate, trimethyl orthoacetate, 2,2-dimethoxypropane,
tetramethoxysilane,
thionyl chloride, trimethylchlorosilane, phosphor us trichloride, phosphorus
pentoxide,
so N,N'-dicyclohexylcarbodiimide, N,N'-dicyclohexylcarbodiimide/N-
hydroxysuccinimide,
N,N'-dicyclohexylcarbodiimide/1-hydroxybenzotriazole, 2-(1H-benzotriazol-1-yl)-
1,1,3,3-
tetramethyluronium tetrafiuoroborate, 2-(1H-benzotriazol-1-yl}-1,1,3,3-tetra-
methyluronium tetrafluoroboratell-hydroxy-benzotriazole, N,N'-
carbonyldiimidazole or
CA 02445571 2003-10-29
-30-
triphenylphosphine/carbon tetrachloride, and optionally with the addition of a
base such
as pyridine, 4-dimethylaminopyridine, N-methylmorpholine or triethylamine,
conveniently at temperatures between 0 and 100°C, preferably at
temperatures
between 0 and 100°C.
In the reactions described above any reactive group present such as hydroxy,
carboxy,
amino, alkylamino or imino groups may be protected during the reaction by
conventional protecting groups which are cleaved again after the reaction (cf.
also T.
Greene, Protective Groups in cJrganic Synthesis, yl/iley Interscience, New
York 1981 ).
For example, a suitable protecting group for a hydroxy group may be the
trimethylsilyl,
acetyl, benzoyl, tert.butyl, trityl, benzyl or tetrahydropyranyl group,
suitable protecting groups for a carboxyl group might be the trimethylsilyl,
methyl, ethyl,
tert.butyl, benzyl or tetrahydropyranyi group,
suitable protecting groups for an amino, alkylamino or imino group might be
the acetyl,
trifluoroacetyl, benzoyl, ethoxycarbonyl, tert.butoxycarbonyl,
benzyloxycarbonyl, benzyl,
methoxybenzyl or 2,4-dimethoxybenzyl group and additionally, for the amino
group, the
2o phthalyl group and
a suitable protecting group for an alkynyl group might be the trimethylsilyl
group.
Any protecting group used may optionally subsequently be cleaved for example
by
hydrolysis in an aqueous solvent, e.g. in water, isoprapanol~wafer,
tetrahydrofuranlwater or dioxanelwater, 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 splitting, e.g. in the presence of iodotrimethylsilane, at temperatures
between 0
so and 100°C, preferably at temperatures between 10 and b0°C.
CA 02445571 2003-10-29
-31 -
A trimethyfsilyl group is cleaved for example by the addition of
tetrabutylammonium
fluoride in a solvent such as tetrahydrofuran or by the addition of pyridinium
fluoride or
using potassium carbonate in methanol.
However, a benzyl, methoxybenzyl or benzyloxycarbonyl group is cleaved
hydrogenolytically, for example, e.g. with hydrogen in the presence of a
catalyst such
as palladium/charcoal in a solvent such as methanol, ethanol, ethyl acetate,
dimethyfformamide, dimethylformamide/acetone or glacial acetic acid,
optionally with
the addition of an acid such as hydrochloric acid at temperatures between 0
and 50°C,
~o but preferably at ambient temperature, and at a hydrogen pressure of 1 to T
bar,
preferably, however, 3 to 5 bar.
A tert.butyl or tert.butyloxycarbonyi group is preferably cleaved by treating
with an acid
such as trifluoroacetic acid or hydrochloric acid, opfiionally using a solvent
such as
~5 water, methyfene chloride, diethyl ether, tetrahydrofuran or dioxane.
An allyloxycarbonyl group is cleaved by treating with a catalytic amount of
tetrakis-
(triphenylphosphine)-palladium(0}, preferably in a solvent such as
tetrahydrofuran and
preferably in the presence of an excess of a base such as morpholine or 1,3-
dimedone
2o at temperatures between 0 and 100°C, preferably at ambient
temperature and under an
inert gas, or by treating with a catalytic amount of tris-(triphenylphosphine)-
rllodium(l)-
chloride in a solvent such as agueous ethanol and optionally in the presence
of a base
such as 1,4-diazabicyclo[2.2.2]octane at temperatures between 20 and
70°C.
25 The compounds of general formulae III to X used as starting materials, some
of which
are known from the literature, are obtained by methods known from the
literature and
the preparation thereof is also described in the Examples.
For example, a compound of general formula III is either commercially
obtainable or
3o can easily be prepared following procedures known from the literature;
a compound of general formula IV may be obtained by reacting a corresponding
aniline,
phenol or thiophenol with a C~~.-alkynyl halide, and
CA 02445571 2003-10-29
-32-
the compounds of general formulae V, Vl, VII and IX may conveniently be
obtained by
conventional methods as described in the present invention.
s l~lloreover, the compounds of general formula I obtained may be resolved
into their
enantiomers andlor diastereomers and the compounds. of general formula I
obtained
with a double bond may be resolved into their cisltrans isomers.
Thus, for example, the compounds of general formula I obtained which occur as
~o racemates may be separated by methods known per sE; (cf. Allinger N. L, and
Eliel E. L.
in °'Topics in Stereochemistry°', Vol. 6, Wiley Interscience,
19r 1 } into their optical
enantiomers and compounds of general formula I with at least 2 asymmetric
carbon
atoms may be resolved into their diastereomers on the basis of their physical-
chemical
differences using methods known per se, e.g. by chromatography and/or
fractional
~5 crystallisation, and, if these compounds are obtained in racemic form, they
may
subsequently be resolved into the enantiomers as mentioned above.
The enantiomers are preferably separated by column separation on chiral phases
or by
recrystallisation from an optically active solvent or by reacting with an
optically active
2o substance which forms salts or derivatives such as e.g. esters or amides
with the
racemic compound, particularly acids and the activated derivatives or alcohols
thereof,
and separating the diastereomeric mixture of salts or derivatives thus
obtained, e.g. on
the basis of their differences in solubility, whilst the free antipodes may be
released
from the pure diastereomeric salts or derivatives by the action of suitable
agents.
25 Optically active acids in common use are e.g. the ~- and L-forms of
tartaric acid or
dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, rnandeiic acrd,
camphorsulphonic acid, glutamic acid, aspartic acid or quinic acid. An
optically active
alcohol may be, for example, (+) or (-)-menthol and an optically active acyl
group in
amides, for example, may be a (+)- or (-)-menthyloxycarbonyl.
Furthermore, the compounds of formula I may be converted info the salts
thereof,
particularly for pharmaceutical use into the physiologically acceptable salts
with
inorganic or organic acids. Acids which may be used for this purpose include
for
CA 02445571 2003-10-29
-3~-
example hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulphonic
acid,
phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid,
tartaric acid or
malefic acid.
s Moreover, if the new compounds of formula 1 contain a carboxy group, they
may
subsequently, if desired, be converted into the salts thereof with inorganic
or organic
bases, particularly for pharmaceutical use into the physiologically acceptable
salts
thereof. Suitable bases for this purpose include for example sodium hydroxide,
potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and
triethanolamine.
As already mentioned, the new compounds of general formula I and the salts
thereof
have valuable properties.
~5 Thus, the compounds of general formula 1 wherein R~ does not contain a
cyano group
have valuable pharmacological properties, particularly an antithrombotic
activity which
is preferably based on an effect on factor Xa, for example on a factor Xa-
inhibiting
activity and on an inhibitory effect on related serine proteases such as e.g.
thrombin,
trypsin, urokinase, factor VIIa, factor IXa, factor Xla and factor Xl la. The
compounds
20 of general formula I wherein R5 contains a cyano group constitute valuable
intermediate
products for preparing the compounds of general formula I wherein R~ denotes
an
optionally substituted aminomethyi or amidino group.
The compounds of Examples 1 to 45 of the present application were investigated
for
25 their effect on the inhibition of factor Xa as follows:
Method: Enzyme-kinetic measurement with chromogenic substrate. The quantity of
p-
nitroaniline (pNA) released from the colourless chromogenic substrate by human
factor
Xa is determined photometrically at 4Q5 nm. It is proportional to the activity
of the
3o enzyme used. The inhibition of the enzyme activity by the test substance
(in relation to
the solvent control) is determined at various concentrations of test substance
and from
this the lC5a is calculated, as the cancentration which inhibits the factor Xa
used by
50 %.
CA 02445571 2003-10-29
-3q._
Material:
Tris(hydroxymethyl)-aminomethane buffer (100 mMol) of and sodium chloride (150
mMol), pH 8.0
Factor Xa {Roche), spec. activity: 10 U/0.5 ml, final concentration: 0.175
Ulml for each
reaction mixture
1o Substrate Chromozym X (Roche), final concentration: 200 pMol/l for each
reaction
mixture
Test substance: final concentration 100, 30, 10, 3, 1, 0.3, 0.1, 0.03, 0.01,
0.003, 0.001
~.Mol/l
Procedure:
10 ~1 of a 23.5-times concentrated starting solution of the test substance or
solvent
{control), 175 p,1 of tris(hydroxymethyl}-aminomethane buffer and 25 p.1 of a
1.65 U/ml
Factor Xa working solution are incubated for 10 minutes at 37°C. After
the addition of
25 ~.( of Chromozym X working solution (1.88 p,Molll) the sample is measured
in a
photometer (SpectraMax 250) at 405 nm for 150 seconds at 37°C.
Evaluation:
1. Determining the maximum increase (deItaOD/minutes) over 3 measuring points.
2. Determining the % inhibition based on the solvent control.
35
3. Plotting a dosage/activity curve (% inhibition vs substance concentration).
4. Determining the ICSO by interpolating the X-value (substance concentration)
of the
dosage/activity curve at Y = 50 % inhibition.
A11 the compounds listed in the experimental section had an (C~o value < 2
~.M.
CA 02445571 2003-10-29
For example, compound 37 was found to have an IC5n value of 4 nM.
The compounds prepared according to the invention are generally well
tolerated.
In view of their pharmacological properties the new cornpounds and the
physiologically
acceptable sans thereof are s~ritable for the prevention and treatment of
venous and
arterial thrombotic diseases, such as for example the treatment of deep leg
vein
thrombosis, for preventing reoccfusions after bypass operations or angioplasty
(PTCA),
and occlusion in peripheral arterial diseases such as pulmonary embolism,
disseminated intravascular coagulation, for preventing coronary thrombosis,
stroke and
the occlusion of shunts. In addition, the compounds according to the invention
are
suitable for antithrombotic support in thrombolytic treatrr~ent, such as for
example with
alteplase, retepiase, tenecteplase, staphyfokinase or stireptokinase, for
preventing long-
term restenosis after PT(C)A, j=or the prevention and treatment of ischaemic
incidents in
~5 patients with all forms of coronary heart disease, for preventing
metastasis and the
growth of tumours and inflammatory processes, e.g: in the treatment of
pulmonary
fibrosis, for preventing and treating rheumatoid arthritis, for preventing and
treating
fibrin-dependent tissue adhesions andlor the formation of scar tissue and for
promoting
wound healing processes. The new compaunds and the physiologically acceptable
salts
2o thereof may be used therapeutically in conjunction with acetylsalicylic
acid, with
inhibitors of platelet aggregation such as fibrinogen receptor antagonists
(e.g.
abciximab, eptifibatide, tirofiban, roxifiban), with physiological activators
and inhibitors of
the clotting system and the recombiant analogues thereof (e.g. Protein C,
TFPI,
antithrombin), with inhibitors of A~P-induced aggregation (e.g. clopidogrel,
ticlopidine),
25 with P2T receptor antagonists (e.g. cangrelor) or with combined thromboxane
receptor
antagonistslsynthetase inhibitors (e.g. terbogrel).
The dosage required to achieve such an effect is appropriately 0.01 to 3
mg/kg,
preferably 0.03 to 1.0 mg/kg by intravenous route, and 0.03 to 30 mg/kg,
preferably
so 0.1 to 10 mglkg 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 andlor diluents, e.g. with corn starch, lactose,
glucose,
CA 02445571 2003-10-29
microcrystalline cellulose, magnesium stearate, polyvir~ylpyrrolidone, citric
acid, tartaric
acid, water, water/ethanoi, waterlgiycerol, water/sorbitol, water/polyethylene
glycol,
propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty
substances such
as hard fat or suitable mixtures thereof, to produce conventional galenic
preparations
such as plain or coated tablets, capsules, powders, su spensions or
suppositories.
The Examples which follow are intended to illustrate the invention without
restricting its
scope:
1 o Examale 1
3- f 3-[4.-(N-acetyl-cyclopentylamino}-3-methyl-
phenyl]propargylamino}benzarnidine-
hydrochloride
~cN~
c / \~
N
HsC H \
NH
H2N * FiCI
a) 3-proparctylamino-benzonitriie
11.8 g (0.1 mol) of 3-aminobenzonitrile and 12.3 ml (0.1 '1 mol) of propargyl
bromide
(80% in toluene) are stirred in 250 mi toluene and 19.2 ml (0.11 mol) of N-
ethyl-
2o diisopropylamine for 18 hours at 90°C. After cooling the .mixture is
diluted with ethyl
acetate and washed with water. The combined organic extracts are dried and
concentrated by evaporation. The residue is chromatographed on silica gel,
eluting with
dichloromethanelethanol in the ratio 98:2.
Yield: 9.9 g (63% of theory),
Rf value: 0.6 (Silica gel; dichloromethanelethanol = 95:5)
~r~pHgN2 (15f.19)
Mass spectrum: (M-H)- = 155
CA 02445571 2003-10-29
_37-
b) 4-cyciopent~lamino-3-methyl-iodobenzene
A mixture of 2.5 g (10.7 mmoi) of 4-iodo-2-methylaniline, 1.0 mf (11.8 mmol)
of cyclo-
pentanone, 0.9 ml (16.1 mmol) of glacial acetic acid arid 0.1 g of p-
toluenesulphonic
acid are stirred in 50 ml tetrahydrofuran for 30 minutes. Then 3.1 g (13.9
mmol) of
s sodium triacetoxyborohydride are added and the mixture is stirred for a
further 26 hours
at ambient temperature. The solvent is distilled off and the residue is
chromatographed
on silica gel, eluting with petroleum etherlethyl acetate 0 to 10%.
Yield: 0.52 g (16% of theory),
1o Rf value: 0.65 {silica gel; petroleum etherlethyl acetate = 9:1 )
G~oF-1~61N (301.17)
Mass spectrum: (M+H)+ = 302
c) 4~,N-acet~rl-cYcioQentylamino)-3-methyi-iodobenzene
1s 0.5 g (1.7 mmol) of 4-cyclopentylamino-3-methyl-iodobenzene are dissolved
in 20 ml
tetrahydrofuran and after the addition of 81.3 rng (1.7 mmol) of sodium
hydride (50% in
oil) stirred for 1 hour at 40 °C. After cooling to ambient temperature
0.1 ml (1.5 mmol) of
acetyl chloride is added and the mixture is stirred overnight at ambient
temperature.
The solvent is distilled off and the residue distributed in waterlethyf
acetate. The
2o combined organic extracts are dried, concentrated by evaporation and
chromatographed on silica gei, eluting with dichloromethanelethanol 0 to
5°J~.
Yield: 0.30 g {57% of theory),
Rf value: 0.40 {silica gel; dichloromethanelethanol = 95:5)
C~4H~$1N0 (343.21)
2s Mass spectrum: (M+H)+ = 344
(M+Na)~ = 366
d) 3-~3-L4-(N-acetyl-cyclopentylamino~-3-methyr-phenyl-~ro~arqvlamino~-
benzonitrile
A mixture of 0.3 g (0.85 mmol) of 4-(N-acetyl-cyclopentylamino)-3-methyl-
iodobenzene,
30 0.4 ml {2.9 mmol) of triethylamine, 97. 6 mg {0.08 mmol) of tetrakis-
triphenylphospine-
paliadium(0) and 16.1 mg (0.085 mmol) of copper-{1)-iodide are refluxed in 10
ml
acetonitrile for 10 minutes. Then 0.2 g (1.2 mmol) of 3-propargylamino-
benzonitrile in 1
ml acetonitrile are added dropwise and refluxed for a further 6 hours. The
solvent is
CA 02445571 2003-10-29
-38-
distilled off. The residue is taken up in ethyl acetate and washed with 15%
sodium
chloride solution. The combined organic extracts are concentrated by
evaporation and
chromatographed on silica gel, eluting with dichloromethanelethanol 0 to 5%.
Yield: 0.32 g (100% of theory),
Rf value: 0.33 (silica gel; dichloromethane/ethanol = 95:5)
C24H25N30 (371.49)
Mass spectrum: (M-I~)- = 370
e) 3-X314-(N-acetyl-cycfopent~rlamino -3-methyl-phenyll-pro~aarqy
lamino~benzamidine-
~Q hydrochloride
A solution of 0.3 g (0.8 mmol) of 3-~3-(4-(N-acetyl-cyciopentyl-amino)-3-
methyl-
phenylJpropargylamino~benzonitrile is stirred in 30 ml of ethanol saturated
with
hydrogen chloride gas first for one hour at 0°C and then for 5 h at
ambient temperature.
The solvent is removed in vacuo at a maximum bath temperature of 30°C
and replaced
~ 5 by 30 ml of abs. ethanol. Then 0.3 g (2.9 mmol) of ammonium carbonate are
added
and the mixture is stirred for 36 hours at ambient temperature. The solvenfi
is distilled
off and the residue is chromatographed on silica gel, eluting with
dichloromethanelethanol 5 to 25%.
Yield: 0.15 g (42% of theory),
2o Rf value: 0.13 (silica gel; dichloromethanelethanol = 4:1 )
C24H2gN40 x HCl (388.52/424.98)
Mass spectrum: (M+H)+ = 389
(M+Cf)- = 423125 (chlorine isotope)
CA 02445571 2003-10-29
-39-
Example 2
4-hydroxy-3-{3-[4-(pyrrolidin-1-yf-carbonyl)-3-methyl-phenyl]-propargyl-
amino-benzamidine-hydrochloride
H3c
0 ~ \ HO
H \
-r~~
H2N * I-~~l
a) 3-methyl-4-(pyrrolidin-1-yl-carbon~rl)-bromobenzene
3.2 g {15 mmol) of 4-bromo-2-methyl-benzoic acid are dissolved in 450 ml of
1o tetrahydrofuran and 50 ml of water and after the addition of 1.3 ml (15.4
mmol) of
pyrrolidine, 5.3 g (16.5 mmol) of O-(benzotriazol-1-yl)-N,~I,N';N'_
tetramethyluroniumtetrafluoroborate {tBtU) and 5.7 ml (33 mmol) of N-
ethyldiisopropyfamine stirred for 19 hours at ambient temperature. The solvent
is
distilled off, the residue is distributed in dichloromethane/water, the
combined organic
extracts are dried and concentrated by evaporation. The crude product is
chromatographed on silica gel, eluting with dichloromethanelethanol 0 to
3°/a.
Yield: 4.0 g {100% of theory),
Rf value: 0.46 (silica gel; dichloromethanelethanol ~ 95:5)
2o b) 3-f3-methyl-4-(pyrrolidin-1-yl-carbonyl)-then I~1-propargyl-alcohol
Prepared analogously to Example 1d from 3-methyl-4.-(pyrrolidin-1-yl-carbonyl)-
bromobenzene, propargylalcohol, tetrakis-triphenyl-phosphine-palladium(0),
copper-(I)-
iodide and triethylamine in acetonitrile.
Yield: 61 °10 of theory,
Rf value: 0.23 (silica gel; dichloromethane/ethanol ~ 95:51
~15H17N~2 (243.31 )
Mass spectrum: (M+H)+ = 244
(M+Na)+ = 266
CA 02445571 2003-10-29
- 40 _
c) 4-hydroxy-3-~3-f4-(pyrrolidin-1-yl-carbonyl)-3-methyl-
~henyl]:propargylarnino~-
benzonitrile
0.6 g (2.5 mmol) of 3-[3-methyl-4-(pyrrolidin-1-yl-carbony!)-phenyl]-
propargylalcohol and
1 ml (2.7 mmol) of triethylamine are dissolved in 15 ml tetrahydrofuran. At a
temperature
of 5-10°C 0.2 ml (2.7 mmol) of methanesulphonic acid chloride are added
dropwise in
ml tetrahydrofuran. After 10 minutes the reaction is allowed to return to
ambient
temperature and stirred for a further 1.5 hours. The solution is poured onto
ice water
and extracted with ethyl acetate. The combined organic extracts are dried and
1o concentrated by evaporation (0.6 g, 78°l0 of theory). The
methanesulphonate which is
not further purified is dissolved in 10 ml dimethylformarnide and after the
addition of 0.3
g (2.3 mmol) of 3-amino-4-hydroxybenzonitrile and 1 ml (5.8 mmol) of N-
ethyldiisopropylamine stirred far 4 hours at 100°C. Then it is diluted
with ethyl acetate
and washed with sodium chloride solution. The combined organic extracts are
~s concentrated by evaporation and chroatographed on silica gel, eluting with
dichloromethane/ethanol 0 to 5%.
Yield: 0.22 g (32% of theory),
Rf value: 0.38 (silica gel; dichloromethane/ethanol = 95:5)
C22~21N3~2 (359.43)
2o Mass spectrum: (M-H)~ = 358
(M+Na)'~ = 382
d) 4-h d~~~3-f4-(~yrrolidin-1- !-c~ arbonyl -3-methyl-~>hen~f~proparqylamino~
benzamidine-hydrochloride
2s Prepared analogously to Example 1a from 4-hydroxy-3-~(3-[4-(pyrrolidin-1-yl-
carbonyl)-3-
methylphenyl]-propargylamino}-benzonitriie, ethanol saturated with hydrogen
chloride
gas and ammonium carbonate.
Yield: 42% of theory
Rf value: 0.07 (silica gel; dichloromethane/ethanol = 4:1;)
3o C~H24N402 x HCl (376.461412.92)
Mass spectrum: (M-H)- = 375
(M+H)+ = 377
(M+Cl)- = 411/13 (chlorine isotope)
CA 02445571 2003-10-29
v _41 _
Example 3
3-{3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-phenyl]-propargylamino}-
benzarnidine-
s hydrochloride
~' HCI
Prepared analogously to Example 1 a from 3-~3-[3-methyl-4-(pyrrolidin-1-yl-
carbonyf)-
1o phenyl]-propargylamino)-benzonitrile9 ethanol saturated with hydrogen
chloride gas and
ammonium carbonate.
Yield: 24% of theory
Rf value: 0.16 (silica gel; dichloromethanelethanol = 4:1 )
~22H24N4~ x HCl (360.46/396.92)
15 I\llass spectrum: (illl+H)* = 3~1
(Ni+CI)- = 395/97 (chlorine isotope)
Example 4
20 3-~N-methyl-3-[3-methyl-4-(pyre-olidin-1-yl-carbony!)-phenyl]-
propargylamino~-
benzamidine-hydrochloride
H3C
O /
N
H3~
-NH
H2N '~ HCI
CA 02445571 2003-10-29
- 42 -
Prepared analogously to Example 1e from 3-{N-methyl-3-[3-methyl-4-(pyrrolidin-
1-yl-
carbonyl)-phenyl-propargylamino~-benzonitrile, ethanol saturated with hydrogen
chloride gas and ammonium carbonate.
Yield: 43% of theory
Rf value: 0.18 (silica gel; dichloromethanelethanoi = 4:1 )
G23H26N4~ x HCI (374.49/410.95)
Mass spectrum: (M+H)~ = 375
(M+CI)- = 409111 (chlorine isotope)
~o Example 5
3-{N-acetyl-3-[3-methyl-4-(pyrrolidin-1-yi-carbonyl)-pherzyl~-propargylamino)-
benzamidine-hydrochloride
H3C
O /
O
CH3 NH
15 H2~ * H~CI
a) 3-(N-acetyl-3-trimeth I~silyl-pro~para lamino -benzonitr~ile
Prepared analogously to Example 1 c from 3-acetylamino-benzonitrile, 3-
trimethylsilyl-
propargyl bromide and sodium hydride in tetrahydrofuran.
2o Yield: 52% of theory
Rf value: 0.67 (silica gel; dichloromethanelethanol = 95:5)
C~5H~$N20si (270.41 )
IVlass spectrum: (M+~i)+ = 271
(M+Na)~ = 293
CA 02445571 2003-10-29
-43-
b) 3-(N-acetyi_proparctylamino -benzonitrile
2.8 g (10.3 mmol} of 3-(N-acetyl-3-trimethylsilyl-propargylamino)-benzonitrile
are
dissolved in 50 ml of methanol and after the addition of 1.3 g (12.4 mmol) of
sodium
carbonate stirred for 2 hours. Then the mixture is filtered and the filtrate
concentrated by
evaporation. The residue is distributed in dichloromethanelwater, the combined
organic
extracts are dried and concentrated by evaporation.
Yield: 1.9 g (91 % of theory),
Rf value: 0.65 (silica gel; dichloromethanelethanoi = 95:5)
C12H1oN2~ (198.21 )
1o Mass spectrum: (M)+ = 198
c) 3-~N-acetyl-3-f3-methyl-4-(pyrrolidin-1-yi-carbonyl)-phenyBl-
~roparqylamino~-
benzonitrile
Prepared analogously to Example 1 d from 3-(N-acetyl-propargylamino)-
benzonitrile, 3-
~5 methyl-4-(pyrrolidin-1-yl-carbonyl)-bromobenzene, tetralkis-
triphenylphosphine-
palladium(0), copper-(I)-iodide and triethylamine in acetonitrile.
Yield: 31 % of theory,
Rf value: 0.42 (silica gel; dichioromethane/ethanoi = 95:5)
C24H23N3~2 (385.47)
2o Mass spectrum: (M+Na)~ = 408
d) 3-~N-acetyl-3-f3-methyl-4-(pyrrolidin-1_-vl-carbonyl)- pllenvll-
t~roparqvlamino~-
benzamidine-hydrochloride
Prepared analogously to Example 1e from 3-{N-acetyl-3-~3-methyl-4-(pyrralidin-
1-yl-
25 carbonyl)-phenyl]-propargylamino}-benzonitrile, ethanol saturated with
hydrogen
chloride gas and ammonium carbonate.
Yield: 73% of theory
Rfvalue: 0.17 (silica gel; dichioromethanelethanol = 4:1;)
C24H2sN442 X HCI (402.50/438.97)
3o Mass spectrum: (M+H)ø = 403
(M+CI}- = 437/39 (chlorine isotope)
CA 02445571 2003-10-29
. -44-
Example 6
3-f4-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-phenyl]-but-3-~inyiamino}-
benzamidine-
hydrochloride
/ \ N~°2
N / \
- ~H
O
'~ HCl
Prepared analogously to Example 1e from 3-{4-[3-methyl-4-(pyrrolidin-1-yl-
carbonyl)-
phenyl3-but-3-inylamino}-benzonitrile, ethanol saturated with hydrogen
chloride gas and
ammonium carbonate.
Yield: 2% of theory
Rf value: 0.15 (silica gel; dichloromethanelethanol = 4:1 )
~23H26N4~ x HCI (374.491410.85)
Mass spectrum: (M+H)ø = 375
Example 7
3-{3-[3-methyl-4-(pyrrolidin-1-yi-carbonyl)-phenyi~-propyl-amino}-benzamidine-
hydrochloride
O H \ /
N~C -N H2
°~N * HCf
mg (75.5 ~.mol) of 3-{3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-phenyl]-
propargylamino}_
benzamidine-hydrochloride are dissolved in 10 ml of ethanol and after the
addition of 15
2s mg of palladium on activated charcoal (10%) at ambient temperature
hydrogenated with
hydrogen. The catalyst is filtered off and the solution concentrated by
evaporation.
CA 02445571 2003-10-29
-45-
Yield: 30 mg (99% of theory),
Rf value: 0.17 (silica gel; dichloromethanelethanol = 4:1 )
C22H28N4O x HCl (364.491400.95)
Mass spectrum: (M)~ = 364
(M+H)~ = 365
(M+CI)- = 399!401 (chlorine isotope)
Example 8
3-~3-(2,5-dimethyl-4-(pyrrofidin-1-y!-carbonyl)-phenyl]-propargylamino}-
benzamidine-
~o hydrochloride
* HCI
Prepared analogously to Example 1 a from 3-{3-[2,5-dirnethy!-4-(pyrrolidin-1-
yl-
carbonyl)-phenyl]-propargylamino)-benzonitrile, ethanol saturated with
hydrogen
chloride gas and ammonium carbonate.
Yield: 11 % of theory
~t~ value: 0.15 (silica gel; dichloromethane/ethanol = 4:1 )
~23H26N4~ x HCI (374.49/410.95)
2o Mass spectrum: (M-H)~ = 373
(M+H)ø = 375
(M+CI)~ = 4(39111 (chlorine isotope)
Exam~ale 9
2s 3-[3-(2'-aminosulphonyi-biphenyl-4-yl~-propargylamino]-benzamidine-
dihydrochloride
CA 02445571 2003-10-29
-46-
/ \ / \
o ~S~o ~ H \ /
H2N NH
H2N * 2 I-ICI
a) N-tert.butyl-benzenesulphonic acid amide
9.6 ml (75 mmol) of benzenesulphonic acid chloride are placed in 100 ml
pyridine and
7.9 ml (75 mmol) of tert.butylamine are added dropwise at 5°C,
whereupon the
temperature increases to 35°C. After the addition has ended the mixture
is stirred for
another hour at 35°C. Then it is poured onto ice water and the
crystalline precipitate is
suction filtered.
Yield: 7.8 g (48% of theory),
Rf value: 0.75 (silica gel; petroleum etherlethyl acetate = 1:1 )
C~pH~5NO2S (213.30)
Mass spectrum: (M-H)' = 212
b) 2-tert-butylaminosulphonyl-benzeneboric acid
1~ 6.0 g (0.028 mol) of N-tert.butylbenzenesulphonic acid amide are dissolved
in 100 ml
tetrahydrofuran and at - 5°C 45 ml of n-butyl-lithium {1.6 molar in
hexane) are added
dropwise. After the addition has ended the mixture is stirred for another hour
at ambient
temperature. Then 7.2 ml (0.03 moI) of triisopropyl borate in 10 ml
tetrahydrofuran are
added dropwise and stirred for 1 hour at 35°C. The reaction solution is
stirred into 200
2o ml of 1 molar hydrochloric acid and extracted with ethyl acetate after 30
minutes. The
ethyl acetate extracts are extracted with 200 ml of 1 molar sodium hydroxide
solution.
The alkaline aqueous phases are then extracted with ethyl acetate, the
combined
organic extracts are dried and concentrated by evaporation. The residue is
chromatographed on silica gel, eluting with petroleum etherlether (25 to 50%).
2s Yield: 3.3 g (46% of theory),
Rf value: 0.2 (silica gel; petroleum etherlethyl acetate = 1:1
C10H16BN~4S (257.12)
Mass spectrum: (M-H)' = 256
CA 02445571 2003-10-29
-4~-
c) 4'-bromobiphenyl-2-sulphonic acid-tart.-but lay mide
0.9 g (3.2 mmol) of 4-bromo-iodobenzene and 0.1 g (0.097 mmol) of
tetrakistriphenylphosphine-palladium(0) are stirred in 10 ml of toluene for 10
minutes at
ambient temperature. Then 0.5 g (1.9 mmol) of 2-tart.-
butyiaminosulphonylbenzeneboric
acid are dissolved in 15 ml of methanol, 2.4 ml (4.8 mmol) of 2 molar sodium
carbonate
solution are added and this suspension is added dropwise. The reaction
solution is
refluxed for 8 hours and stirred overnight at ambient temperature. The organic
phase is
separated off, extracted again with dichloromethane, them combined organic
extracts are
dried and concentrated by evaporation. The residue is chromatographed on
silica gel,
~o eluting with dichloromethane.
Yield: 0.60 g (52% of theory),
Rf value: 0.82 (silica gel; dichloromethanefethanol = 95:5)
C16H18BrN02S (368.30)
Mass spectrum: (M-H)- = 366168 (bromine isotope)
(M+Na)~ = 390192 (bromine isotope}
d) 3-f3-~2'-tart.butylaminosulphonyl-biphen,r~l-4-yl -~ropargylaminol-
benzonitrile
Prepared analogously to Example 1 d from 4'-bromobiphenyl-2-sulphonic acid-
tert.-
butylamide, 4-propargylamino-benzonitrile, triethylamine, tetrakis-
triphenylphosphine-
2o palladium(0) and copper-())-iodide in acetonitrile.
Yield: 39% of theory,
Rf value: 0.58 (silica gel; dichloromethanefethanol = 95:5)
C26H25N3~2S (4'43.57}
Mass spectrum: (M-H)- = 442
25 (M+Na)+ = 466
e) 3-f3- 2'-aminosul~phonyl-biphenyl-4yl~i~roparqylamino]~benzamidine-
dihydrochloride
Prepared analogously to Example 1 a from 3-(3-(2°-tart.buty!-
aminosulphonyl-biphenyl-4.-
yl}-propargylamino]-benzonitrile, ethanol saturated with hydrogen chloride gas
and
3o ammonium carbonate.
Yield: 33% of theory
Rf value: 0.43 (Reversed phase RP 8; methanoUS% sodium chloride
solution = 6:4)
CA 02445571 2003-10-29
- 48 -
C22H2oN4~2S x 2 HCI {404.491477.41 )
Mass spectrum: (M+H)+ = 405
(M+Cl)- = 439/41 (Chlorine Isotope)
s Exampie 10
3-{3-[3-methyl-4-(pyrrof idin-1-yl-carbonyl)-phenyl]-propargyl-oxy}-
benzamidine-
hydrochloride
H3C
0 0
~' HCI
a) 3-(3 j3-meth~~l-4-{pyrrolidin-1-yl-carbonyl)-phenylj-prol~arg~~~}-
benzonitrile
Prepared analogously to Example 2c from 3-[3-methyl-4-(pyrrolidin-1-yl-
carbonyl)-
phenyl]-propargylalcohol and methanesulphonic acid chloride and subsequent
treatment
with 3-hydroxybenzonitrile and N-ethyldiisopropylamine in dimethylformamide.
Yield: 64% of theory,
Rf value: 0.38 (silica gel; dichloromethanelethanol = 95:5)
~22H20N2~2 (3.42)
Mass spectrum: (M+Na)+ = 367
b) ~3-[3-meth I-4- pyrroiidin-1-yl-carbonyl)-phenyll-pro~arqyl-oxy)-
benzamidine-
hydrochloride
Prepared analogously to Example 1e from 3-(3-[3-methyl-4-(pyrroiidin-1-yl-
carbonyl)-
phenyl]-propargyloxy}-benzonitrile, ethanol saturated with hydrogen chloride
gas and
ammonium carbonate.
Yield: 65% of theory
Rf value: 0.19 (silica gel; dichloromethanelethanol = 4:1 )
c22H23N3~2 x HCi (361.451397.92)
CA 02445571 2003-10-29
_q.g_
Mass spectrum: (M+H)+ = 362
(M+Cl)- = 396198 (chlorine isotope)
ExamJ~le 11
3-{1-methyl-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-phenyl]-propargylamino}-
benzamidine-hydrochloride
H3C
N ' \ CH3
H
-NH
HZN * HCl
a) 3-methyl~~yrrolidin-1-yl-carbonyl)-bromobenzene
Prepared analogously to Example 2a from 4-bromo-2-methylbenzoic acid,
pyrrolidine,
tBtU and N-ethyl-diisopropylamine in tetrahydrofuranlwater 9:1
Yield: 98% of theory,
Rf value: 0.46 (silica gel; dichloromethane/ethanol = 95:5)
C~2H~4BrN0 (268.15)
b) 1-methyl-3-(3-methy~pyrrolidin-1-yl-carbonyl)~hen~l-aropargylalcoho(
2o Prepared analogously to Example 1 d from 3-methyl-4-(pyrrolidin-1-yl-
carbonyl)-
bromobenzene, 3-butyn-2-ol-tetrakis-triphenyl-phosphine-palladium(0), copper-
(I)-
iodide and triethylamine in acetonitrile.
Yield: 90% of theory,
Rf value: 0,48 (silica gel; dichloromethane~ethanof = 95:5)
C~6H19~~2 (257.33)
Mass spectrum: (M+H)~ = 258
CA 02445571 2003-10-29
_5(~_
c) 1-methyl-3-f3-methyl-4-(pyrrofidin-1-ylicarbonyf)phenylLproparayl-bromide
0.95 g (3.7 mmol) of 1-methyl-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)phenyl]-
propargyl-
alcohol are dissolved in 10 ml acetonitrile and after the addition of 0.66 g
(4.0 mmol) of
N,N'-carbonyldiimidazole stirred for 30 minutes at ambient temperature. Then
1.6 ml
(18.5 mmol) of allylbromide are added and the mixture is refluxed for 3 hours.
After
cooling to ambient temperature it is diluted with ether. T'he organic phase is
washed
with water and saturated sodium chloride solution, dried over sodium sulphate
and
concentrated by evaporation.
Yield: 1 g (86% of theory)
1o Rf value: 0.5 (silica gel; dichloromethane/ethanol = 95:5)
G~6lH~aBrNO (320.23)
Mass spectrum: (M+H)+ = 320/22 (bromine isotope)
d) 3-f1-methyl-3 j3-methyl-4-(pyrrolidin-1-yl-carbonyl-phenyil-~ropargylamino~-
benzonitrile
A mixture of 1 g (3.1 mmol) of 1-methyl-3-[3-methyl-4-(pyrrolidin-1-yl-
carbonyl)phenyl]-
propargyi-bromide, 0.4 g (3.4 mmol) of 3-aminobenzonitrile and 5 ml of N-
ethyldiisopropylamine are refluxed in 10 m1 tetrahydrofuran for 13 hours.
After cooling
the mixture is diluted with ethyl acetate, the organic extracts are washed
with water,
zo dried over sodium sulphate and concentrated by evaporation. The residue is
chromatographed on silica gel, eluting with dichloromethanelmethanol 98:2.
Yield: 0.78 g (70% of theory)
Rf value: 0.3 (silica gel; dichloromethanelethanol = 95:5)
C23H23N3~ (357.46)
Mass spectrum: (M+H)+ = 358
e) 3-~1-methyl-3-f3-methyf-4-(pyrrolidin-1-vl-carbonyl)-ph~nvll-
oroaarqvlamino)-
benzamidine-hydrochloride
Prepared analogously to Example 1 a from 3-~1-methyl-;!-[3-methyl-4-
(pyrrolidin-1-yl-
3o carbonyl)-phenyl]-propargylamino}-benzonitrile, ethanol :saturated with
hydrogen
chloride gas and ammonium carbonate.
Yield: 67% of theory
Rf value: 0.24 (silica gel; dichloromethanelethanol = 4:1 )
CA 02445571 2003-10-29
-51 -
~23H26N4~ x HCI (374.49/410.95)
Mass spectrum: {M+H)+ = 375
(M+CI)- = 409111 (chlorine isotope)
Example 12
3-{N-ethoxycarbonylmethyl-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-phenyl]-
propargylamino}-benzamidine-hydrochloride
/ \
o N
~O NH
~O H2N
~o H3c ~ HCf
a) 3-(N-ethoxycarbonylmeth I~- gropargylamin~-benzonitrile
A mixture of 0.78 g {5 mmol) of 3-propargylamino-benzonitrile, 0.55 m) (5
mmol) of ethyl
15 brom~acetate and 0.2 g (5 mmol) of magnesium oxide are stirred in 20 ml of
dimethylacetamide for 6 days at 75 °C. Then the mixture is filtered,
the filtrate is diluted
with ethyl acetate and washed with water. The combined organic extracts are
dried and
concentrated by evaporation. The residue is chromatographed on silica gei,
eluting with
dichloromethane.
2o Yield: 1 g (83°/~ of theory)
Rf value: 0.61 (silica gel; dichloromethane/ethanol = 95:5)
C14H14N2o2 (242.28)
Mass spectrum: (M+H)+ = 243
2~ b) ~N-ethoxycarbonylmett~l-3-f3-methyl-4-(pyrrolidin-1-~,~rl-carbonyl)-
,~henyll-
proparaylamino~-benzonitrile
Prepared analogously to Example 1d from 3-(N-ethoxycarbonylethyl-N-
propargylamino)-benzonitrile, 3-methyl-4-(pyrrolidin-1-yl-c;arbonyl)-
iodobenzene,
CA 02445571 2003-10-29
-52-
tetrakis-triphenyl-phosphine-palladium(0), copper-(I)-iodide and triethylamine
in
acetonitrile. The crude product was further reacted direc;tiy
Rt value: 0.43 (silica gel; dichloromethanelethanol = 95:5)
G2~H27N3O3 (429.52)
Mass spectrum: (M+H)+ = 430
c) 3-$N-ethoxycarbonylmethyl-3-[3-methyl-~p~rrrofidin-1-yl-carbonyl)-phenyls-
aropargylamino~-benzamidine-hydrochloride
Prepared analogously to Example 1 a from 3-{N-ethoxycarbonylmethyl-3-[3-methyl-
4-
(pyrrolidin-1-yl-carbonyl)-phenyl]-propargylamino}-benzonitrile, ethanol
saturated with
hydrogen chloride gas and ammonium carbonate.
Yield: 21 % of theory
Rf value: 0.1 (silica gel; dichioromethane/ethanol = 4:1
C26H3oN4O3 X HCI (446.56/483.02)
Mass spectrum: (M-~H)+ = 447
(M+CI)- = 481/83 (chlorine isotope)
Example 13
3-{N-methyl-3-[4-(N-acetyl-cyclopentylamino)-3-methyl-phenyl]propargylamino}-
benzamidine-hydrochloride
* HCf
Prepared analogously to Example 1 a from 3-{N-methyl-~3-[4-(N-acetyl-
cyclopentylamino)-3-methyl-phenyl]propargylamino}ben:7onitrile, ethanol
saturated with
hydrogen chloride gas and ammonium carbonate.
Yield: 30% of theory
CA 02445571 2003-10-29
-53-
Rf value: 0.15 (silica gel; dichloromethanelethanol = 4:1 )
~25H30N4~ x HCI (402.55/439.01 )
Mass spectrum: (M+H)+ = 403
(M+Cl)' = 437139 (chlorine isotope)
Example 14
3-{N-hyd roxycarbonylmethyl-3-[3-methyl-4-{pyrrolidin-1-yl-carbonyl)-phenyl]-
propargylamino}-benzamidine-hydrochloride
NH
Ho ~2N * HCI
0.3 g {0.62 mmol) of 3-{N-ethoxycarbonylmethyl-3-[3-methyl-4-(pyrroiidin-1-yl-
carbonyl)-
phenyl]-propargylamino}-ben~amidine-hydrochloride arE: stirred in 10 ml of 6
molar
hydrochloric acid for 4 days at ambient temperature. The hydrochloric acid is
distilled
off.
Yield: 0.28 g {99% of theory)
Rf value: 0.52 (Reversed phase RP 8; methanol / 5% sodium chloride solution =
6:4)
~24~"i26N4d3 x HCI (418.50/454.96)
2o Mass spectrum: (M+H)ø = 419
(M-H)' = 417
CA 02445571 2003-10-29
-54-
Example 15
3-{N-methyl-3-{4-[N-(3-ethoxycarbonyl-propionyl)-cyciopenty(amino]-3-methyl-
phenyl}-
propargylamino}benzamidine-hydrochloride
s
N~
~ '-c~3 * HCI
Prepared analogously to Example 1e from 3-{N-methyl-3-{4-[N-(3-ethoxycarbonyl
propionyl)-cyclopentylamino]-3-methyl-phenyl}propargylamino}benzonitrile,
ethanol
1o saturated onith hydrogen chloride gas and ammonium carbonate.
Yield: 45°/~ of theory
Rf value: 0.34 (silica gel; dichforomethanelethanol = 4:1 )
~29H36N4~3 x HCI (4'$$.651525.1 ~)
Mass spectrum: (M+H)+ = 439
Example 16
3-{N-methyl-3-{4-[N-(2-ethoxycarbonyl-acetyl}-cyclopeni:ylamino]-3-methyl-
phenyl}propargylamino}benzamidine-hydrochloride
~3~
N
O N
H3C;
O =NH
O~ HzN
20 CH3 * 1-ICI
CA 02445571 2003-10-29
-55-
Prepared analogously to Example 1 a from 3-~N-methyl-3-~4-[N-(2-ethoxycarbonyl-
acetyl)-cyclopentylamino]-3-methyl-phenyl}propargylamino}benzonitrile,
efihano!
saturated with hydrogen chloride gas and ammonium carbonate.
Yield: 57% of theory
Rf value: 0.23 (silica gel; dichloromethanelethanol = 4:1 )
C2gH3~N4O3 X HCI (474.611511.07)
Mass spectrum: (M+H)ø = 475
(M+CI)- = 509111 (chlorine isotope)
1o Example 17
3-~N-methyl-3-~4-[N-(2-hydroxycarbonyl-acetyl)-cyclopentyiamino]-3-methyl-
phenyl}-
propargylamino}benzamidine-hydrochloride
\ /
~ 5 off °~2N ~ HCI
Prepared analogously to Example 14 from 3-~N-methyl-3-~4-[N-(2-ethoxycarbonyl-
acetyl)-cycfopentylamino]-3-methyl-phenyl}propargylamino}benzamidine-hyd
rochloride
and 6 molar hydrochloric acid.
2o Yield: 100% of theory
Rf value: 0.43 (Reversed phase RP 8; methanol I 5% sodium chloride solution =
6:4)
C2gH3pNq.~3 X HCI (44.561483.02)
Mass spectrum: (M+H)+ = 447
(M-H)- = 445
25 (M+CI)- = 481183 (chlorine isotope)
CA 02445571 2003-10-29
_ 55 ..
Example 18
3-{3-[4-(pyrrolidin-1-yl-carbonyl)-phenyl-propargylaminca}-benzamidine-
hydrochloride
H
-~F!
H2N *' I-ICI
Prepared analogously to Example 1e from 3-~3-[4-(pyrralidin-1-yl-carbonyl)-
phenylj-
propargylamino}-benzonitrile, ethanol saturated with hydrogen chloride gas and
ammonium carbonate.
1o Yield: 54% of theory
Rf value: 0.15 (silica gel; dichlaromethane/ethanoi = 4:1 )
~21H22N4~ x HCI {346.44/382.90)
Mass spectrum: (M+N)ø = 347
(M+CI)- = 381/83 (chlorine isotope)
Examcle 19
3-f N-methyl-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-phenyi~-propyl-amino-
benzamidine-
hydrochloride
~H
H2N * ICI
CA 02445571 2003-10-29
_ 57 -
Prepared analogously to Example 7 from 3-{N-methyl-3-[3-methyl-4-(pyrrolidin-1-
yl-
carbonyl)-phenyl]-propargylamino}-benzamidine-hydrocllloride, palladium on
activated
charcoal (10%) and hydrogen in ethanol.
Yield: 84% of theory
Rfvalue: 0.15 (silica gel; dichloromethanelethanol =4:1;)
C23H30N4~ x HCI (378.53/414.99)
Mass spectrum: (M+H)* = 379
(M+CI)- = 413/15 (chlorine isotope)
1o Example 20
3-{N-methyl-3-[3-methyl-4-(2,5-dihydropyrroi-1-yl-carbonyl)-phenyl]-
propargylamino}-
benzamid ine-hydrochloride
/ \
~ \ /
N2~ * HCI
Prepared analogously to Example 1a from 3-{N-methyl-3-[3-methyl-4-(2,5-
dihydropyrrol-1-yl-carbonyl)-phenyl]-propargylamino}-ber~zonitri1e, ethanol
saturated
with hydrogen chloride gas and ammonium carbonate.
2o Yield: 83% of theory
Rf value: 0.15 (silica gel; dichloromethane/ethanol = 4:1 )
C23H24N4d x HCI (372.481408.94)
Mass spectrum: (M+H)+ = 373
(M+CI)- = 407/09 (chlorine isotope)
CA 02445571 2003-10-29
-58-
Example 21
3-{3-[3-methyl-4-{2,5-d i hyd ropyrrol-1-yl-carbonyl )-phenyl-p rope rgyla
mino}-
benzamidine-hydrochloride
N
O X30 H
=NH
H2N * HCI
Prepared analogously to Example 1 a from 3-{3-[3-methyl-4-(2,5-dihydropyrrol-1-
yl-
carbonyl)-phenyl]-propargylamino}-benzonitrile, ethanol saturated with
hydrogen
chloride gas and ammonium carbonate.
Yield: 22% of theory
Rf value: 0.15 (silica gel; dichloromethanefethanol = 4:1 )
C22H22N40 x HCI (358.45/394.91 )
Mass spectrum: (M+H)+ = 359
~ 5 (M+CI)~ = 393/95 (chlorine isotope)
Example 22
3-[N-methyl-3-(4-isopropylcarbonyl-3-methyl-phenyl)-propargylamino]-
benzamidine-
2o hydrochloride
H3C
O N ~ ~
=N
H2N * HCI
CA 02445571 2003-10-29
-59-
a) 4-isopropylcarbonyl-3-methyl-bromobenzene
0.58 g (24 mmol) of magnesium fragments are added to 10 ml diethyl ether, then
2 ml
(21.3 mmol) of isopropyl bromide followed by 2 g (10 mmol) of 4-bromo-2-
methylbenzonitrile in 10 ml diethyl ether are added dropwise. The reaction
mixture is
s maintained at ambient temperature for 1 h and refluxed for 15 hours. After
cooling, it is
carefully combined with ice water and acidified with 1 molar sulphuric acid.
Then it is
stirred for 1 hour at 80°C, cooled and extracted with dichloromethane.
The combined
organic extracts are dried over sodium sulphate and concentrated by
evaporation.
Yield: 2.3 g (96% of theory)
1o Rf value: 0.14 (Reversed phase RP 8; methanol / 5% sodium chloride solution
= 6:4)
C~~H~3Br0 (241.13)
Mass spectrum: (M+H)+ = 241143 (bromine isotope}
b) 3-jN-methy~4-isopro~pylcarbonyi-3-methyl-phenyl~~ropartwlamino]-
benzonitrile
15 Prepared analogously to Example 1 d from 4-isopropylcarbonyl-3-methyl-
bromobenzene, 3-(methyl-propargylamino)-benzonitrile, tetrakis-
triphenylphosphine-
palladium(0}, copper-(I)-iodide and triethylamine in acetonitriie.
Yield: 27% of theory
Rf value: 0.64 (silica gel; dichloromethar~elethanol = 98:2)
2o C~H22N20 (330.43)
Mass spectrum: (M+H)+ = 331
(M+Na)+ = 353
c) 3- N-meth I-3- 4-iso ro Icarbon 1-3-meth 1- hen t - ro ar lamina -
benzamidine-
25 hydrochloride
Prepared analogously to Example 1 a from 3-(N-methyl-3-(4-isopropylcarbonyl-3-
methyl-phenyl)-propargylamino]-benzonitrile, ethanol saturated with hydrogen
chloride
gas and ammonium carbonate.
Yield: 65% of theory
so Rf value: 0.31 (silica gel; dichloromethanelethanol = 4:1 )
C22H25N30 x HCl (347.47/383.93)
Mass spectrum: (M+H)+ = 348
(M+CI)- = 382/84 (chlorine isotope)
CA 02445571 2003-10-29
-so-
Example 23
3-{N-benzyl-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-phenyl]-propargylamino~-
s benzamidine-hydrochloride
/ \
~ N3C ~ / \ ~N \ /
~NM
H2N * HCI
Prepared analogously to Example 1 a from 3-(N-benzyl-3-[3-methyl-4-(pyrrolidin-
1-yl-
~o carbonyl)-phenylj-propargylarnino}-benzonitrile, ethanol saturated with
hydrogen
chloride gas and ammonium carbonate.
Yield: 50% of theory
Rt value: 0.27 (silica gel; dichloromethane/ethanol = 4:1
C2gH3pN~O x HCI (450.601487.05)
15 Mass spectrum: (M+H)+ = 451
(M+CI)- = 485/87 (chlorine isotope)
Example 24
20 3-~N-methyl-3-[3-methyl-4-(N-methyl-propargylamino-carbonyl)-phenyl]-
propargyl-
amino}-benzamidine-hydrochloride
NH
* HCI
CA 02445571 2003-10-29
_61 _
Prepared analogously to Example 1 a from 3-~N-methyl-3-[3-methyl-4-(N-methyl-
propargylamino-carbonyl)-phenyl]-propargylamino)-ben:zonitrile, ethanol
saturated with
hydrogen chloride gas and ammonium carbonate.
Yield: quantitative
Rf value: 0.19 (silica gel; dichloromethane/ethanol = 4:1 )
C23H24N4~ X HCI (372.48/408.94)
Mass spectrum: (M+H)~ = 373
1o Example 25
3-~N-methyl-3-[4-(N-allyl-methylamino-carbonyl)-3-methyl-phenyl]-
propargylamino}-
benzamidine-hydrochloride
~zN * i-ICI
Prepared analogously to Example 1 a from 3-(N-methyl-3-[4-(N-allyl-methylamino-
carbonyl)-3-methyl-phenyl]-propargylamino}-benzonitrile, ethanol saturated
with
hydrogen chloride gas and ammonium carbonate.
2o Yield: quantitative
Rf value: 0.23 (silica gel; dichloromethane/ethanol ~ 4:1 )
C23H26N4~ X I'ICI (374.50/410.95)
Mass spectrum: (M+H)* = 315
CA 02445571 2003-10-29
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Example 26
3-~N-methyl-3-[4-(N-ethyl-methylamino-carbonyl~3-methyl-phenyl]-
propargylamino}-
benzamidine-hydrochloride
H3C-N
O N
1~3C HOC
=NH
H2N * HCi
Prepared analogously to Example 1 a from 3-{N-methyl-~3-[4-(N-ethyl-
methylamino-
carbonyl)- 3-methyl- phenyl]-propargylamino~-benzonitrile, ethanol saturated
with
1o hydrogen chloride gas and ammonium carbonate.
Yield: quantitative
R~ value: 0.19 (silica gel; dichloromethane/ethanol = 4:1 )
C22H2~N40 x HCI (362.48/398.94)
11/lass spectrum: (M+H)+ = 363
Example 27
3-(N-methyl-3-[4-(N-isopropyl-methylamino-carbonyl)-3-methyl-phenyl]-propargyl-
amino}-benzamidine-hydrochloride
H3C
--CN3
H3C N /
O N
=N~..~
H2N * HCI
CA 02445571 2003-10-29
- 68 _
Prepared analogously to Example 1 a from 3-{N-methyl-3-[4-(N-isopropyl-
methylamino-
carbonyl)-3-methyl-phenyl]-propargylamino}-benzonitrile, ethanol saturated
with
hydrogen chloride gas and ammonium carbonate.
Yield: 68% of theory
Rg value: 0.1 (silica gel; dichlorornethanefethanol = 9:1 )
C23H2gN~O x HCI (37fi.51/412.97)
Mass spectrum: (M+H)~ = 376
Example 28
. 10
3-{N-methyl-3-[2'-aminosulphonyl-biphenyl-4.-yl]-propargylamino}-benzamidine-
hydrochloride
/ \ / \
N \ /
S=O H3C
H2N =NH
H2N * WCI
Prepared analogously to Example 1e from 3-{N-methyl-3-[2'-
tert.butylaminosulphonyl-
biphenyl-4-yl]-propargylamino}-benzonitrile, ethanol saturated with hydrogen
chloride
gas and ammonium carbonate.
Yield: quantitative
2o Rf value: 0.13 (silica gel; dichloromethanelethanol = 9:1 )
C231"i22N4~2S X I"IC) (418.531454.99)
Mass spectrum: (M+H)* = 419
(M-H)- = 417
CA 02445571 2003-10-29
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Example 29
3-[N-methyl-3-(4-diethylaminocarbonyl-3-methyl-pheny!)-propargylamino]-
benzamidine-
hydrochloride
H3C,
H3 ~
N ~ \
H3C H3C
NH
H2N * H~:l
Prepared analogously to Example 1e from ~-[N-methyl-3-(4.-diethylaminocarbonyl-
3-
methyl-phenyl)-propargylamino]-benzonitrile, ethanol saturated with hydrogen
chloride
1 o gas and ammonium carbonate.
Yield: 8% of theory
Rf value: 0.29 (silica gel; dichloromethane/ethanol = 4:1 )
C23H28N40 x HCI (376.51/412.97)
Mass spectrum: (M+H)* = 377
Exam Ip a 30
3-{N-(2-ethoxycarbonylethyl)-3-[3-methyl-4.-(pyrrolidin-1-yl-carbonyl)-phenyl]-
propargylamino~-benzamidine-hydrochloride
o N
H3C
O~ -NH
O~ H2N
cH3 * I-pCl
CA 02445571 2003-10-29
-65-
Prepared analogously to Example 1 a from 3-{N-(2-ethoxycarbonylethyl)-3-[3-
methyl-4-
(pyrrofidin-1-yl-carbonyl)-phenyl]-propargylamino)-benzonitrile, ethanol
saturated with
hydrogen chloride gas and ammonium carbonate.
Yield: 52% of theory
Rf value: 0.22 (silica gel; dichloromethane/ethanol = 4:1 )
~27H32N4~3 x HCI (460.59/49'.05)
Mass spectrum: (M+H)+ = 461
(M+C1)' = 495197 (chlorine isotope)
1o Example 31
3-{N-(2-ethoxycarbonylethyl)-3-[3-methyl-4-(2,5-dihydropyrrol-1-yl-carbonyl)-
phenyl]-
propargyiamino)-benzamidine-hydrochloride
N / \
o N \ ~
H3 ,~''
O~ =NH
O~ H2N
cH3 * HCI
Prepared analogously to Example 1 a from 3-{N-(2-ethoxycarbonylethyl)-3-[3-
methyl-4-
(2,5-dihydropyrrol-1-yl-carbonyl)-phenyl]-propargylamino)-benzonitrile,
ethanol
saturated with hydrogen chloride gas and ammonium carbonate.
Yield: 49% of theory
2o Rf value: 0.22 (silica gel; dichforomethanelethanol = 4:1 )
C27H30N4~3 x HCI (458.57/495.03)
Mass spectrum: (M+H)+ = 459
(M+CI)- = 493/95 (chlorine isotope)
CA 02445571 2003-10-29
Example 32
3-{N-(4-ethoxycarbonylphenylmethyl)-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-
phenylj-
propargyiamino}-benzamidine-hydrochloride
H2N
-NH
/ \
O N
H3C
~--CH
3
o * HCI
Prepared analogously to Example 1e firom 3-{N-(4.-ethoxycarbonylphenylmethyl)-
3-[3-
methyl-4.-(pyrroiidin-1-yl-carbonyl)-phenylj-propargylamino}-benzonitrile,
ethanol
saturated with hydrogen chloride gas and ammonium carbonate.
Yield: 38°l0 ofi theory
1o Rf value: 0.38 (silica gel; dichloromethane/ethanoi = ~.:1 )
~32H34N4o3 x HCi (522.66/559.12)
Mass spectrum: (M+H)ø = 523
(M+Cl)- = 557
Example 33
3-{N-(3-methoxycarbonylphenylmethyl)-3-r3-methyl-4-(pyrrolidin-1-yl-carbonyl)-
phenylj-
propargylamino)-benzamidine-hydrochloride
/ \
0
H3C
3
20 * HCl
CA 02445571 2003-10-29
-67-
Prepared analogously to Example 1 a from 3-(N-(3-methoxycarbonylphenylmethyl)-
3-[3-
methyl-4-(pyrrolidin-1-yl-carbonyl)-phenyl]-propargylamino}-benzonitrile,
ethanol
saturated with hydrogen chloride gas and ammonium carbonate.
Yield: 71 % of theory
Rf value: 0.28 (silica gel; dichloromethane/ethanol = 4:1 )
~!31H32N4o3 x HCi {508.641545.09)
Mass spectrum: (M+H)+ = 509
(M+CI)' = 543145 (chlorine isotope)
1o Example 34
3-{N-{4-hydroxycarbonylphenylmethyl)-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl }-
phenyl~-
propargylamino}-benzamidine-hydrochloride
H2N
=NH
° CN v ~
~3~
° * HCI
° 15
Prepared analogously to Example 14 from 3-~N-(4-ethoxycarbonylphenyimethyl)-3-
[3-
methyl-4-(pyrrolidin-1-yf-carbonyl}-phenyl)-propargylamir~o}-benzamidine-
hydrochloride
and 6 molar hydrochloric acid.
Yield: quantitative
2o Rf value: 0.25 (Reversed phase RP 8; methanol I 5% sodium chloride solution
= 6:4)
C30H30N4C'3 x HCI (494.611531.06)
Mass spectrum: (M+H)+ = 495
(M-H)' = 493
CA 02445571 2003-10-29
- 68 _
Example 35
3-{N-(3-hydroxycarbonylphenylmethyl)-3-[3-methyl-4-(pyrroiidin-1-yl-carbonyl)-
phenyl]-
propargylamino}-benzamidine-hydrochloride
* HCI
Prepared analogously to Example 14 from 3-{N-(3-methoxycarbonylphenylmethyl)-3-
[3-
methyl-4-(pyrrolidin-1-yl-carbonyl)-phenyl]-propargylamino}-benzamidine-
hydrochloride
and 6 molar hydrochloric acid.
Yield: 69% of theory
Rf value: 0.24 (Reversed phase RP 8; methanol l 5% sodium chloride solution =
6:4)
~30H30N4o3 x HCI (494,61/531.06)
~liass spectrum: (M+H)* = 495
(M-H)- = 493
Example 36
3- f N-(2-hydroxycarbonylethyl)-3-[3-methyl-4-(pyrrol id in-1-yl-carbonyl)-
phenyl]-
propargylamino}-benzamidine-hydrochloride
/ \
'N \ /
~3~
O~ NH
off u2~ * HCi
CA 02445571 2003-10-29
-69-
Prepared analogously to Example 14 from 3-{N-(2-ethoxycarbonylethyl)-3-[3-
methyl-4-
(pyrrolidin-1-yl-carbonyl}-phenyi~-propargyiamino}-benzamidine-hydrochloride
and 6
molar hydrochloric acid.
Yield: quantitative
Rf value: 0.41 (Reversed phase RP 8; methanol I 5% sodium chloride solution =
6:4)
C2~H2gN4O3 X HCI (432.54/468.99)
Mass spectrum: (M+H)+ = 433
(M-H)- = 431
(M+CI)~ = 467169 (chlorine isotope}
Example 37
3-{N-benzyl-3-(3-methyl-4.-(2,5-dihydropyrrol-1-yl-carbonyl)-phenyl]-
propargylamino}-
benzamidine-hydrochloride
H2N
NH
O H3C ~ ~ N
* HCI
Prepared analogously to Example 1 a from 3-{N-benzyl-3-(3-methyl-4-(2,5-
dihydropyrroi-1-yl-carbonyl)-phenyl]-propargylamino~-benzonitrile, ethanol
saturated
2o with hydrogen chloride gas and ammonium carbonate.
Yield: 13% of theory
Rf value: 0.38 (silica gel; dichloromethanelethanol = 3:1
C2gH2gN4Q x HCI (448.581485.04)
Mass spectrum: {M+H)+ = 449
(M+CI)- = 483/85 (chlorine isotope)
CA 02445571 2003-10-29
- 70 _
Example 38
3-[N-benzyl-3-(4-isobutyryl-3-methyl-phenyl)-propargylamino]-benzamidine-
hydrochloride
CH3 H2N
H3C / \ \ NH
o H3C / ~ N
* Hcl
Prepared analogously to Example 1 a from 3-[N-benzyl-3-(4-isobutyryl-3-methyl-
phenyl)-propargylamino]-benzonitrile, ethanol saturated with hydrogen chloride
gas and
~o ammonium carbonate.
Yield: 77% of theory
R.f value: 0.44 (silica gef; dichloromethanelethano( = 3:1 }
C2aH2gN30 x HCl {423.57/460.03}
Mass spectrum: (M+H)* = 424
(M+CI}- = 458/60 (chlorine isotope}
Example 39
3-[N-benzyl-3-{4-benzoyl-3-methyl-phenyl)-propargylamino]-benzamidine-
hydrochloride
NH
* I-ICI
Prepared analogously to Example 1 a from 3-[N-benzyl-?.-(4-benzoyl-3-methyl-
phenyl)-
propargylamino]-benzonitrile, ethanol saturated with hydrogen chloride gas and
ammonium carbonate.
Yield: 75% of theory
CA 02445571 2003-10-29
-71 -
Rt value: 0.47 (silica gel; dichioromethanelethanoi = 3:~1 )
~31H27N3o x HCI (457.59/494.05)
Mass spectrum: (M+H)+ = 458
(M+CI)' = 492194 (chlorine isotope)
EXample 40
3-{N-benzyl-3-[2'-aminosulphonyl-biphenyl-4-yl]-propargyiamino}-benzamidine-
hydrochloride
1Q
/ \ / \ - _\
/ \ N \ /
O..--~S=O
H2N NH
H2N * HCI
Prepared analogously to Example 1e from 3-{N-benzyl-3-[2'-
tert.butylaminosulphonyi-
biphenyl-4-yl]-propargylamino}-benzonitrile, ethanol saturated with hydrogen
chloride
gas and ammonium carbonate.
Yield: 10% of theory
Rf value: 0.45 (silica gel; dichloromethane/ethanoi = 3:1 )
C2gH2gNq.~2~ x HCI (494.62/531.08)
Mass spectrum: (M+H)+ = 495
(M-H)~ = 493
(M+CI)- = 529131 (chlorine isotope)
CA 02445571 2003-10-29
_~~_
Example 41
3-{N-benzyl-3-[2'-aminosulphonyl-biphenyl-4-yl]-propylamino)-benzamidine-
hydrochloride
* HCI
Prepared analogously to Example 7 from 3-{N-benzyl-3-[2'-aminosulphonyl-
biphenyl-4-
yl]-propargylamino}-benzamidine-hydrochloride, palladium on activated charcoal
(10%)
1o and hydrogen in ethanol.
Yield: 100% of theory
Rf value: 0.18 (Reversed phase RP 8; methanol l 5% sodium chloride solution =
6:4)
C29H3aN4O2S x HCl (498.65/535.11 )
Mass spectrum: (M+H)~ = 499
(M+CI)- = 533135 (chlorine isotope)
Example 42
3-{N-(pyrid in-2-ylmethyl)-3-[3-methyl-4-(pyrrol id in-1-yl-carbonyl)-phenyl]-
propargyl-
2o amino}-benzamidine-dihydrochloride
/ \
° / \ N \ /
H3C
N NH
HZN * 2 HCI
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-73-
Prepared analogously to Example 1 a from 3-{N-(pyridin-2-yimethyl}-3-[3-methyl-
4-
(pyrrolidin-1-yl-carbonyl)-phenyl]-propargylamino)-benzonitrile, ethanol
saturated with
hydrogen chloride gas and ammonium carbonate.
Yield: 20% of theory
Rf value: 0.15 (silica gel; dichloromethanelethanol = 95:5)
C2gH2gN5~ x 2 HC1 (451.571524.49)
Mass spectrum: (M+H}+ = 452
Example 43
3-{N-(pyridin-3-ylmethyl}-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-phenyl]-
propargy(-
amino}-benzamidine-dihydrochloride
~3c ~ / \ ~ \ /
N ~IH
H2~ * 2 HCI
Prepared analogously to Example 1 a from 3-{N-(pyridin-3-ylmethyf)-3-[3-methyl-
4-
(pyrrolidin-1-yl-carbonyl}-phenyl]-propargyfarr~ino}-benzonitrile, ethanol
saturated with
hydrogen chloride gas and ammonium carbonate.
Yield: 25% of theory
2o R~ value: 0.13 (silica gel; dichloromethane/ethanof = 95:5}
C2$H29N~0 x 2 HCI (451.57/524.49}
Mass spectrum: (M+H}+ = 452
(M+CI)~ = 486188 (chlorine isotope)
CA 02445571 2003-10-29
-74-
Example 44
3-[N-{2-ethoxycarbonylethyl)-8-(4-cyclopentylcarbony!-3-methylphenyl)-
propargyl-
arnlno]-benzamidine-hydrochloride
CH3 * HCl
Prepared analogously to Example 1 a from 3-[N-(2-ethoxycarbonylethyl)-3-(4-
cyclopentyl-carbonyl-3-methylphenyl)-propargylamlno]-benzonitrile, ethanol
saturated
1o with hydrogen chloride gas and ammonium carbonate.
Yield: 18% of theory
Rf value: 0.19 (silica gel; dichloromethanelethanol = 4:1 )
~!28H33~3~3 x HCI (459.591496.05)
Mass spectrum: (M+H)* = 460
~5 (M+C!)~ = 494196 (chlorine isotope)
Example 45
3-[N-(4-ethoxycarbonylphenylmethyl)-3-{2"-aminosulphonylbipheny!-4.-yl]-
propargyl-
2o amino]-benzamidine-hydrochloride
/ \ / \
o s-o
H2N
3
a * HCi
CA 02445571 2003-10-29
' -75-
Prepared analogously to Example 1 a from 3-[lV-(4-ethoxycarbonylpheny(methyl)-
3-(2~-
tert.butylaminosulphonylbiphenyl-4-yl)-propargylamino]-benzonitrile, ethanol
saturated
with hydrogen chloride gas and ammonium carbonate.
Yiefd: 26°la of theory
Rf value: 0.18 (silica gel; dichloromethanelethanol = 4:1 )
~32H30~4~4S x HCl (566.691603.145)
Mass spectrum: (M+H)+ = 567
(M-H)' = 565
~o (M+Cf)~ = 601103 (chlorine isotope)
Exam~fe 46
~ry ampoule containing 75 mg of active substance per 10 ml
Composition:
Active substance 75.0 mg
2o Mannitol 50.0 mg
water for injections ad 10.0 ml
Preparation:
Active substance and mannitol are dissolved in water. After packaging the
solution is
freeze-dried. To produce the solution ready far use for injections, the
product is
dissolved in water.
3o Example 47
~ry ampoule containing 35 mg of active substance per 2 ml
Composition:
CA 02445571 2003-10-29
-76-
Active substance 35.0 mg
Mannitol 100.0 mg
water for injectionsad 2.0 ml
Preparation:
Active substance and mannitoi are dissolved in water. After packaging, the
solution is
freeze-dried.
To produce the solution ready for use for injections, the product is dissolved
in water.
15
Example 48
Tablet containing 50 mg of active substance
Composition:
(1 ) Active substance 50.0 mg
(~) Lactose 98.0 mg
(3) Maize starch 50.0 mg
(4) Polyvinylpyrrolidone 15.0 mg
(5) Magnesium stearate 2.0 m~
215.0 mg
2s 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,
bipianar,
faceted on both sides and with a dividing notch on one side.
3o Diameter of the tablets: 9 mm.
Example 49
Tablet containing 350 mg of active substance
Composition:
(1 ) Active substance 350.0 mg
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-77-
(2) Lactose 136.0 mg
(3) Maize starch 80.0 mg
(4) Polyvinylpyrrolidone . 30.0 mg
(5) Magnesium stearate 4.0 ma
fi00.0 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,
bipianar,
faceted on both sides and with a dividing notch on one .side.
1o Diameter of the tablets: 12 mm.
Example 50
~5 capsules containing 50 mg of active substance
Composition:
(1 ) Active substance 50.0 mg
20 (2) Dried maize starch58.0 mg
(3) Powdered lactose 50.0 mg
(4) Magnesium stearate 2.0 mp
160.0 mg
25 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 gelatine capsules in a capsule
filling
3o machine.
Exam Ip a 51
Capsules containing 350 mg of active substance
Composition:
(1 ) Active substance 350.0 mg
(2) Dried maize starch 46.0 mg
CA 02445571 2003-10-29
_7g~_
(3} Powdered lactose 30.0 mg
(4) Magnesium stearate 4.0 mg
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 gelatine capsules in a capsule
filling
1o machine.
Example 52
Suppositories containing 100 mg of active substance
1 suppository contains:
Active substance 100.0 mg
Polyethyleneglycol (M.W. 1500) 600.0 mg
2o Polyethyleneglycol (M.W. 6000) 460.0 mg
Polyethylenesorbitan monostearate 840.0 mg
2,000.0 mg
Preparation:
The polyethyleneglycof is melted together with polyethylenesorbitan
monostearate. At
40°C the ground active substance is homogeneously dispersed in the
melt. This is then
cooled to 38°C and poured into slightly chilled suppository moulds.
CA 02445571 2003-10-29
