NOVEL HETEROCYCLYL-METHYL-SUBSTITUTED PYRAZOLES

NOUVEAUX PYRAZOLES HETEROCYCLIQUES METHYL-SUBSTITUES

English Abstract

The invention relates to novel heterocyclyl-methyl-substituted pyrazole
derivatives, to methods for producing them and to their use as medicaments,
especially as medicaments for treating cardiovascular diseases.

French Abstract

L'invention concerne de nouveaux dérivés du pyrazole hétérocycliques méthyl-substitués, leur procédé de fabrication et leur utilisation comme médicaments, notamment pour le traitement des maladies cardiovasculaires.

Claims

-71-
claims
1. Heterocyclyl-methyl-substituted pyrazoles of the general formula (I)
<IMG>
in which
R1 represents a 6-membered aromatic heterocycle having up to 3 nitrogen
atoms, which is optionally substituted up to 2 times in an identical or
different manner by hydrogen, formyl, carboxyl, hydroxyl, mercapto,
straight-chain or branched acyl, alkoxy, alkylthio or alkoxycarbonyl
each having up to 6 carbon atoms, nitro, cyano, azido, halogen, phenyl
and/or is substituted by a group of the formula
-NR4R5
in which
R4 and R5 are identical or different and denote hydrogen or straight-
chain or branched acyl having up to 6 carbon atoms or straight-chain
or branched alkyl having up to 6 carbon atoms, which is optionally
substituted by cycloalkyl having 3 to 6 carbon atoms, hydroxyl, amino
or by straight-chain or branched alkoxy, acyl or alkoxycarbonyl each
having up to 5 carbon atoms,
or

-72
R4 and R5, together with the nitrogen atom, form a 3- to 7-membered
saturated or partially unsaturated heterocycle, which can optionally
additionally contain an oxygen or sulfur atom or a radical of the
formula -NR6,
in which
R6 denotes hydrogen or straight-chain or branched alkyl having up
to 4 carbon atoms,
and/or is substituted by straight-chain or branched alkyl having up to 6
carbon
atoms, which for its part can be substituted by hydroxyl, amino, halogen,
carboxyl, straight-chain or branched acyl, alkoxy, alkoxycarbonyl or
acylamino each having up to 5 carbon atoms or by a radical of the formula -
OR7,
in which
R7 denotes straight-chain or branched acyl having up to 5 carbon atoms or
a group of the formula-SiR8R9R10,
in which
R8, R9 and R10 are identical or different and denote aryl having 6 to 10
carbon
atoms or alkyl having up to 6 carbon atoms,
and/or is optionally substituted by a radical of the formula

-73-
<IMGS>
or S(O)c NR12R13
in which
b and b' are identical or different and denote a number 0, 1, 2
or 3,
a denotes a number 1, 2 or 3,
R11 denotes hydrogen or straight-chain or branched alkyl
having up to 4 carbon atoms,
c denotes a number 1 or 2 and
R12 and R13 are identical or different and denotes hydrogen or
straight-chain or branched alkyl having up to 10 carbon
atoms, which is optionally substituted by cycloalkyl
having 3 to 8 carbon atoms or by aryl having 6 to 10
carbon atoms, which for its part can be substituted by
halogen or
denote aryl having 6 to 10 carbon atoms, which is
optionally substituted by halogen or
denote cycloalkyl having 3 to 7 carbon atoms

-74-
or
R12 and R13, together with the nitrogen atom, form a 5- to 7-
membered saturated heterocycle, which can optionally
contain a further oxygen atom or a radical -NR14,
in which
R14 denotes hydrogen, straight-chain or branched
alkyl having up to 4 carbon atoms or a radical of
the formula
<IMG>
or denotes benzyl or phenyl, where the ring systems
are optionally substituted by halogen,
and
the 6-membered aromatic heterocycle R1, which contains up to
3 nitrogen atoms, is substituted 1 to 3 times in an identical or
different manner by
(A) straight-chain or branched alkyl having 7 to 20 carbon
atoms, straight-chain or branched alkenyl having up to 20
carbon atoms and 1 to 2 double bonds,
straight-chain ar branched alkinyl having up to 20 carbon atoms and 1
to 2 triple bonds,

-75-
where alkenyl and alkinyl have a double or triple bond at the
linkage point to the heterocycle R1,
cycloalkoxy having 3 to 14 carbon atoms,
or optionally substituted aryl having 6 to 10 carbon atoms,
where the alkyl, alkenyl, alkinyl, cycloalkoxy and aryl radicals
mentioned for their part are optionally substituted and if aryl = phenyl
are compulsorily substituted by formyl, carboxyl, hydroxyl, mercaptyl,
nitro, cyano, azido, halogen, straight-chain, branched or cyclic alkyl,
acyl, acylamino, alkoxy, alkylthio, alkoxycarbonyl each having up to 6
carbon atoms,
by aryl having 6 to 10 carbon atoms, which is optionally substituted by
halogen, alkyl, alkoxy each having 1 to 6 carbon atoms,
by 5- to 6-membered hetaryl, having 1 to 3 heteroatoms from the
series N, O, S, SO, SO2, which is optionally substituted by halogen,
alkyl, alkoxy each having 1 to 6 carbon atoms,
and/or
by a group of the formula
-NR a R b
in which
R a and R b are identical or different and denotes hydrogen or straight-
chain or branched acyl having up to 10 carbon atoms, cyclic
acyl having 3 to 8 carbon atoms, straight-chain or branched

-76-
alkyl having up to 10 carbon atoms or cycloalkyl having 3 to
14 carbon atoms, where these are optionally substituted by
hydroxyl, amino, monoalkylamino, dialkylamino or by
straight-chain or branched alkoxy, acyl or
alkoxycarbonyl each having up to 5 carbon atoms,
or
R a and R b together with the nitrogen atom form a 3- to 7-membered
saturated or partially unsaturated heterocycle, which is
optionally substituted by
hydroxyl and which optionally additionally contains an
oxygen or sulfur atom or a radical of the formula -NR c,
in which
R c denotes hydrogen or straight-chain or branched
alkyl having up to 4 carbon atoms,
and/or
by a group of the formula
-OR d
in which
R d denotes straight-chain or branched acyl having up to 5 carbon
atoms or a group of the formula -SiR e R f R g,

-77-
in which
R e, R f and R g are identical or different and denote aryl having
6 to 10 carbon atoms or alkyl having up to 6 carbon
atoms,
and/or
(B) is substituted by a 3- to 14-membered heterocyclic ring, which can be
saturated or unsaturated and contains 1 to 4 heteroatoms from the
series N, O, S, SO, SO2 and optionally by
halogen, phenyl, cyano, alkyl, alkoxy each having 1 to 6 carbon atoms,
-NR h R i,
where
R h and R i can be identical or different and denote hydrogen, straight-
chain, branched or cyclic alkyl or acyl having up to 6 carbon
atoms
or
R h and R i together with the nitrogen atom form a 3- to 7-membered
saturated or partially unsaturated heterocycle, which optionally
additionally contains an oxygen or sulfur atom or a radical of
the formula -NR j,
in which

-78-
R j denotes hydrogen or straight-chain or branched alkyl
having up to 4 carbon atoms,
and/or
(C) is substituted by straight-chain or branched alkyl having up to 6
carbon atoms, which is compulsorily substituted by one or more of the
following groups
formyl, mercaptyl, nitro, cyano, cyclic acyl having 3 to 14 carbon
atoms, straight-chain or branched acyl having 6 to 14 carbon atoms,
alkoxy having 6 to 14 carbon atoms, acylamino having 6 to 14 carbon
atoms, alkoxycarbonyl having 6 to 14 carbon atoms, alkylthio having
up to 14 carbon atoms, cyclic alkyl having 3 to 14 carbon atoms,
phenyl, which is optionally substituted by
halogen, alkyl having up to 6 carbon atoms or alkoxy having
up to 6 carbon atoms;
5- to 6-membered hetaryl having 1 to 3 heteroatoms from the series N,
O, S, SO, SO2, which is optionally substituted by halogen, alkyl
having up to 6 carbon atoms or alkoxy having up to 6 carbon atoms;
-NR k R l, where one of the radicals R k and R l can be hydrogen and the
other or both independently of one another denote straight-chain or
branched acyl having up to 10 carbon atoms, cyclic alkyl having 3 to
14 carbon atoms or R k and R l together with the nitrogen atom form a
3- to 7-membered saturated or partially unsaturated heterocycle, which
optionally additionally contains an oxygen or sulfur atom or a radical
of the formula -NR m,
in which

-79-
R"' denotes hydrogen or straight-chain or branched alkyl having up
to 4 carbon atoms;
and/or
(D) is substituted by alkoxy having up to 6 carbon atoms, which for its
part is substituted,
by hydroxyl, -NR n R °, where R n and R ° can be identical or
different
hydrogen or straight-chain, branched or cyclic alkyl or acyl each
having up to 6 carbon atoms or R n and R ° together with the nitrogen
atom form a 3- to 7-membered saturated or partially unsaturated
heterocycle, which optionally additionally contains an oxygen or
sulfur atom or a radical of the formula -NR p,
in which
R p denotes hydrogen or straight-chain or branched alkyl having up
to 4 carbon atoms,
and/or
(E) is substituted by halogen-substituted acyl having up to 14 carbon
atoms, acyloxy having up to 14 carbon atoms, arylthio having 6 to 10
carbon atoms, where the aryl radical is optionally substituted by
halogen, alkyl, alkoxyl each having 1 to 6 carbon atoms;
heteroarylthio, by 5- to 6-membered hetaryl having 1 to 3 heteroatoms
from the series N, O, S, SO, SO2, which is optionally substituted by
halogen, straight-chain or branched alkyl or alkoxy having 1 to 6
carbon atoms,

-80-
and/or
(F) is substituted by a radical of the formula
-SO2Rq or -SOR r,
where
R q and R r denote straight-chain or branched alkyl having 1 to 10
carbon atoms, cyclic alkyl having 3 to 14 carbon atoms,
aryl having 6 to 10 carbon atoms, which is optionally substituted by
halogen, alkyl having 1 to 6 carbon atoms or alkoxy having 1
to 6 carbon atoms,
or 5- to 6-membered hetaryl having 1 to 3 heteroatoms from the series
N, O, S, SO, SO2, which is optionally substituted by
halogen, straight-chain or branched alkyl having 1 to 4 carbon
atoms or alkoxy having 1 to 4 carbon atoms,
and/or
(G) is substituted by a radical -SO3H
and/or
(H) is substituted by a radical -CON=C(NH2)2 or -C=NH(NH2)
and/or
(I) is substituted by a radical -CONR5Rt

-81-
where
R s and R t can be identical or different and denote hydrogen, straight-
chain or branched alkyl having 1 to 14 carbon atoms or
cycloalkyl having 3 to 14 carbon atoms,
where said alkyl or cycloalkyl radicals are optionally
substituted by cycloalkyl having 3 to 6 carbon atoms, hydroxyl,
amino, straight-chain or branched alkoxy, acyl or
alkoxycarbonyl each having up to 6 carbon atoms,
aryl having 6 to 10 carbon atoms, which is optionally
substituted by halogen, straight-chain or branched alkyl having
1 to 6 carbon atoms, cycloalkyl having 3 to 14 carbon atoms,
alkoxy having 1 to 6 carbon atoms,
or 5- to 6-membered heterocyclyl having 1 to 3 heteroatoms
from the series N, O, S, SO, SO2, which is optionally
substituted by halogen, straight-chain or branched alkyl having
1 to 6 carbon atoms, cycloalkyl having 3 to 14 carbon atoms,
alkoxy having 1 to 6 carbon atoms,
and/or
R s and R t denote aryl having 6 to 10 carbon atoms, which is optionally
substituted by halogen, straight-chain or branched alkyl having
1 to 6 carbon atoms, cycloalkyl having 3 to 14 carbon atoms,
alkoxy having 1 to 6 carbon atoms,
and/or

-82-
R s and R t denote 3- to 10-membered saturated, partially unsaturated or
completely unsaturated heterocyclyl having 1 to 5 heteroatoms
from the series N, O, S; SO, SO2, which is optionally
substituted by halogen, straight-chain or branched alkyl having
1 to 6 carbon atoms, cycloalkyl having 3 to 14 carbon atoms,
alkoxy having 1 to 6 carbon atoms,
and/or
R s and R t, together with the nitrogen atom, form a 3- to 7-membered
saturated or partially unsaturated heterocycle, which optionally
additionally contains an oxygen or sulfur atom or a radical of
the formula -NR u,
where:
R u denotes hydrogen or a straight-chain or branched alkyl
having up to 4 carbon atoms,
and/or
(J) is substituted by a radical of the formula -NR v R w,
where
R v and R w can be identical or different and denote straight-chain or
branched acyl having 7 to 14 carbon atoms, cyclic acyl having
3 to 6 carbon atoms, -SO2-alkyl having 1 to 4 carbon atoms,
hydroxymethyl, hydroxyethyl, alkoxycarbonyl having up to 5
carbon atoms, alkoxyalkyl having a total of up to 8 carbon
atoms, acyloxymethyl having up to 6 carbon atoms in the acyl

-83-
radical (preferably pivaloyloxymethyl) or the following
radicals
<IMGS>
R x-O-CH(R y)-O-CO- ,
<IMG>
in which

-84-
R x and R y are identical or different and denote hydrogen or
straight-chain or branched alkyl having up to 4 carbon
atoms,
m denotes a number 0, 1 or 2 and
R z denotes straight-chain or branched alkyl having up to 6
carbon atoms or cycloalkyl having 3 to 8 carbon atoms,
or one of the radicals R V and R W can optionally be hydrogen,
and/or
(K) is substituted by a radical of the formula -PO(OR)(OR')
where
R and R' denote identical or different straight-chain, branched
or cyclic alkyl having up to 8 carbon atoms or aryl
having 6 to 10 carbon atoms or benzyl,
R2 and R3, including the double bond, form a phenyl ring, which are
optionally substituted up to 3 times in an identical or different
manner by formyl, mercaptyl, carboxyl, hydroxyl, amino,
straight-chain or branched acyl, alkylthio, alkoxy,
alkoxycarbonyl each having up to 6 carbon atoms, nitro,
cyano, azido, halogen, phenyl or straight-chain or branched
alkyl having up to 6 carbon atoms, which for its part can be
substituted by hydroxyl, amino, carboxyl, straight-chain or
branched acyl, alkoxy or alkoxycarbonyl each having up to 5
carbon atoms, or are optionally substituted by a group of the
formula -S(O)c'NR12.R13., in which c~, R12~ and R13' have the

-85-
meaning of c, R12 and R13 indicated above and are identical
or different to these,
A represents phenyl or a 5- to 6-membered aromatic or saturated
heterocycle having up to 3 heteroatoms from the series S, N
and/or O, which is optionally substituted up to 3 times in an
identical or different manner by mercaptyl, hydroxyl, formyl,
carboxyl, straight-chain or branched acyl, alkylthio,
alkyloxyacyl, alkoxy or alkoxycarbonyl each having up to 6
carbon atoms, nitro, cyano, trifluoromethyl, azido, halogen,
phenyl or straight-chain or branched alkyl having up to 6
carbon atoms, which for its part can be substituted by
hydroxyl, carboxyl, straight-chain or branched acyl, alkoxy or
alkoxycarbonyl each having up to 5 carbon atoms,
and/or is substituted by a group of the formula -(CO)d-NR15R16,
in which
d denotes a number 0 or 1,
R15 and R16 are identical or different and denote hydrogen, phenyl,
benzyl or straight-chain or branched alkyl or acyl each having
up to 5 carbon atoms,
their isomeric forms and salts and their N-oxides.
2. Compounds according to claim 1 of the general formula (I), in which
R1 represents a radical of the formula

-86-
<IMGS>
which are optionally substituted up to 2 times in an identical or
different manner by hydrogen, formyl, carboxyl, hydroxyl, straight-
chain or branched acyl, alkoxy or alkoxycarbonyl each having up to 5
carbon atoms, nitro, cyano, azido, fluorine, chlorine, bromine, phenyl
and/or by a group of the formula -NR4R5,
in which
R4 and R5 are identical or different and denote hydrogen or straight-
chain or branched acyl having up to 4 carbon atoms or straight-chain
or branched alkyl having up to 4 carbon atoms, which is optionally
substituted by hydroxyl, amino or by straight-chain or branched alkoxy
having up to 3 carbon atoms, or
R4 and R5 together with the nitrogen atom form a morpholine ring or a
radical of the formula
<IMG>
and/or are substituted by straight-chain or branched alkyl having up to
5 carbon atoms, which for its part can be substituted by hydroxyl,
amino, fluorine, carboxyl, straight-chain or branched acyl, alkoxy,
alkoxycarbonyl or acylamino each having up to 4 carbon atoms or by a
radical of the formula -OR7,

-87-
in which
R7 denotes straight-chain or branched acyl having up to 4 carbon
atoms,
and/or optionally are substituted by a radical of the formula
<IMGS>
in which
b and b' are identical or different and denote a number 0, 1, 2 or 3,
a denotes a number 1, 2 or 3,
R11 denotes hydrogen or straight-chain or branched alkyl having up
to 3 carbon atoms,
and the 6-membered aromatic heterocycles mentioned above under R1
are substituted 1 to 3 times in an identical or different manner by
(A) straight-chain or branched alkyl having 7 to 14 carbon
atoms,straight-chain or branched alkenyl having up to 14
carbon atoms having a double bond,
straight-chain or branched alkinyl having up to 14 carbon
atoms and a triple bond,
where alkenyl and alkinyl have a double or triple bond
at the linkage point to the heterocycle R1,

-88-
cycloalkyloxy having 3 to 8 carbon atoms,
or substituted phenyl,
where said alkyl, alkenyl, alkinyl and cycloalkyloxy radicals
for their part are optionally substituted and the phenyl radical is
compulsorily substituted by carboxyl, hydroxyl, mercaptyl,
nitro, cyano, azido, fluorine, chlorine, bromine, straight-chain,
branched or cyclic alkyl, acyl, acylamino, alkoxy, alkylthio,
alkoxycarbonyl, each having up to 6 carbon atoms,
by aryl having 6 to 10 carbon atoms, which is optionally
substituted by fluorine, chlorine, bromine, alkyl, alkoxy each
having 1 to 6 carbon atoms,
by 5- to 6-membered hetaryl, having 1 to 3 heteroatoms from
the series N, O, S, which is optionally substituted by fluorine,
chlorine, bromine, alkyl, alkoxy each having 1 to 6 carbon
atoms,
and/or
by a group of the formula
-NR a R b
in which
R a and R b are identical or different and denotes hydrogen or
straight-chain or branched acyl having up to 6 carbon
atoms, cyclic acyl having 3 to 6 carbon atoms, straight-
chain or branched alkyl having up to 6 carbon atoms or

-89-
cycloalkyl having 3 to 8 carbon atoms, where these are
optionally substituted by
hydroxyl, amino, monoalkylamino, dialkylamino or by
straight-chain or branched alkoxy, acyl or alkoxy-
carbonyl each having up to 4 carbon atoms,
or
R a and R b together with the nitrogen atom form a 3- to 7-
membered saturated heterocycle,
which optionally additionally contains an oxygen or
sulfur atom or a radical of the formula -NR c,
in which
R c denotes hydrogen or straight-chain or branched
alkyl having up to 3 carbon atoms,
and/or by a group of the formula
-OR d
in which
R d denotes straight-chain or branched acyl having up to 4
carbon atoms,
and/or

-90-
(B) are substituted by a 3- to 8-membered heterocyclic ring, which
can be saturated or unsaturated and contains 1 to 4 heteroatoms
from the series N, O, S and optionally by
fluorine, chlorine, bromine, phenyl, cyano, alkyl, alkoxy each
having 1 to 6 carbon atoms, -NR h R i,
where
R h and R i can be identical or different and denote hydrogen,
straight-chain, branched or cyclic alkyl or acyl having
up to 4 carbon atoms
or
R h and R i, together with the nitrogen atom, form a 3- to 7-
membered saturated heterocycle, which optionally
additionally contains an oxygen or sulfur atom or a
radical of the formula -NR j,
in which
R j denotes hydrogen or straight-chain or branched
alkyl having up to 4 carbon atoms,
and/or
(C) are substituted by straight-chain or branched alkyl having up to
6 carbon atoms, which is compulsorily substituted by one or
more of the following groups

-91-
mercaptyl, nitro, cyano, cyclic acyl having 3 to 8 carbon atoms,
straight-chain or branched acyl having 6 to 10 carbon atoms,
alkoxy having 6 to 10 carbon atoms, acylamino having 6 to 10
carbon atoms, alkoxycarbonyl having 6 to 10 carbon atoms,
alkylthio having up to 10 carbon atoms, cyclic alkyl having 3
to 8 carbon atoms,
phenyl, which is optionally substituted by
fluorine, chlorine, bromine, alkyl having up to 6 carbon
atoms or alkoxy having up to 6 carbon atoms;
5- to 6-membered hetaryl having 1 to 3 heteroatoms from the
series N, O, S, which is optionally substituted by fluorine,
chlorine, bromine, alkyl having up to 6 carbon atoms or alkoxy
having 1 to 6 carbon atoms;
-NR k R l, where one of the radicals R k and R l can be hydrogen
and the other or both independently of one another denote
straight-chain or branched acyl having up to 6 carbon atoms,
cyclic alkyl having 3 to 8 carbon atoms or R k and R l, together
with the nitrogen atom, form a 3- to 7-membered saturated
heterocycle, which optionally additionally contains an oxygen
or sulfur atom or a radical of the formula -NR m,
in which
R m denotes hydrogen or straight-chain or branched alkyl
having up to 4 carbon atoms,
and/or
(D) are substituted by alkoxy having up to 6 carbon atoms, which
for its part is substituted by

-92-
hydroxyl, -NR n R o, where R n and R o can be identical or
different hydrogen or straight-chain, branched or cyclic alkyl or
acyl each having up to 5 carbon atoms or R n and R o together
with the nitrogen atom form a 3- to 7-membered saturated
heterocycle, which optionally additionally contains an oxygen
or sulfur atom or a radical of the formula -NR p,
in which
R p denotes hydrogen or straight-chain or branched alkyl
having up to 3 carbon atoms,
and/or
(E) are substituted by halogen-substituted acyl having up to 10
carbon atoms, acyloxy having up to 10 carbon atoms, arylthio
having 6 to 10 carbon atoms, where the aryl radical is
optionally substituted by fluorine, chlorine, bromine, alkyl,
alkoxyl each having 1 to 6 carbon atoms, heteroarylthio, by 5-
to 6-membered hetaryl having 1 to 3 heteroatoms from the
series N, O or S, which is optionally substituted by fluorine,
chlorine, bromine, straight-chain or branched alkyl or alkoxy
having 1 to 6 carbon atoms,
and/or
(F) are substituted by a radical of the formula
-SO2R q or -SOR r,
where

-93-
R q and R r denote straight-chain or branched alkyl having 1 to 6
carbon atoms, cyclic alkyl having 3 to 8 carbon atoms,
aryl having 6 to 10 carbon atoms, which is optionally
substituted by fluorine, chlorine, bromine, alkyl having
1 to 6 carbon atoms or alkoxy having 1 to 6 carbon
atoms,
or 5- to 6-membered hetaryl having 1 to 3 heteroatoms from
the series N, O, S, which is optionally substituted by
fluorine, chlorine, bromine, straight-chain or branched
alkyl having 1 to 4 carbon atoms or alkoxy having 1 to
4 carbon atoms,
and/or
(G) are substituted by a radical -SO3H
and/or
(I) are substituted by a radical -CONR5R t
where
R5 and R t can be identical or different and denote hydrogen,
straight-chain or branched alkyl having 1 to 10 carbon
atoms or cycloalkyl having 3 to 8 carbon atoms,
where said alkyl or cycloalkyl radicals are optionally
substituted by cycloalkyl having 3 to 6 carbon atoms,
hydroxyl, amino, straight-chain or branched alkoxy,

-94-
acyl or alkoxycarbonyl each having up to 5 carbon
atoms,
aryl having 6 to 10 carbon atoms, which is optionally
substituted by fluorine, chlorine, bromine, straight-
chain or branched alkyl having 1 to 5 carbon atoms,
cycloalkyl having 3 to 8 carbon atoms, alkoxy having 1
to 6 carbon atoms;
or 5- to 6-membered heterocyclyl having 1 to 3
heteroatoms from the series N, O, S, which is optionally
substituted by fluorine, chlorine, bromine, straight-
chain or branched alkyl having 1 to 6 carbon atoms,
cycloalkyl having 3 to 8 carbon atoms, alkoxy having 1
to 6 carbon atoms,
and/or
R s and R t denote aryl having 6 to 10 carbon atoms, which is
optionally substituted by fluorine, chlorine, bromine,
straight-chain or branched alkyl having 1 to 6 carbon
atoms, cycloalkyl having 3 to 8 carbon atoms, alkoxy
having 1 to 6 carbon atoms,
and/or
R s and R t denote 3- to 8-membered saturated heterocyclyl
having 1 to 3 heteroatoms from the series N, O, S;
which is optionally substituted by fluorine, chlorine,
bromine, straight-chain or branched alkyl having 1 to 6

-95-
carbon atoms, cycloalkyl having 3 to 8 carbon atoms,
alkoxy having 1 to 6 carbon atoms,
and/or
R s and R t together with the nitrogen atom form a 3- to 7-
membered saturated heterocycle, which optionally
additionally contains an oxygen or sulfur atom or a
radical of the formula -NR u,
where
R u denotes hydrogen or a straight-chain or branched
alkyl having up to 4 carbon atoms,
(J) are substituted by a radical of the formula -NR v R w
where
R v and R w can be identical or different and denote straight-
chain or branched acyl having 7 to 10 carbon atoms,
cyclic acyl having 3 to 6 carbon atoms, -SO2-alkyl
having 1 to 4 carbon atoms, hydroxymethyl,
hydroxyethyl, alkoxycarbonyl having up to 5 carbon
atoms, alkoxyalkyl having a total of up to 8 carbon
atoms, acyloxymethyl having up to 6 carbon atoms in
the acyl radical (preferably pivaloyloxymethyl) or the
following radicals
<IMGS>

-96-
<IMGS>
R x -O-CH(R y)-O-CO- ,
<IMG>
in which
R x and R y are identical or different and denote
hydrogen or straight-chain or branched alkyl
having up to 3 carbon atoms
m denotes a number 0, 1 or 2 and

-97-
R Z denotes straight-chain or branched alkyl having
up to 4 carbon atoms, cyclopropyl, cyclopentyl
or cyclohexyl,
or one of the radicals R V and R W can optionally be
hydrogen,
(K) are substituted by a radical of the formula -PO(OR)(OR')
where
R and R' denotes identical or different straight-chain, branched
or cyclic alkyl having up to 6 carbon atoms or aryl
having 6 to 10 carbon atoms or benzyl,
R2 and R3, including the double bond, form a phenyl ring, which are
optionally substituted up to 3 times in an identical or different manner
by formyl, carboxyl, hydroxyl, amino, straight-chain or branched acyl,
alkoxy, or alkoxycarbonyl each having up to 5 carbon atoms, nitro,
cyano, azido, fluorine, chlorine, bromine, phenyl or straight-chain or
branched alkyl having up to 5 carbon atoms, which for its part can be
substituted by hydroxyl, amino, carboxyl, straight-chain or branched
acyl, alkoxy or alkoxycarbonyl each having up to 4 carbon atoms,
A represents phenyl or represents tetrahydropyranyl, furyl,
tetrahydrofuryl, morpholinyl, pyrimidyl, piperazinyl or pyridyl, which
is optionally substituted up to 2 times in an identical or different
manner by hydroxyl, formyl, carboxyl, straight-chain or branched acyl,
alkylthio, alkyloxyacyl, alkoxy or alkoxycarbonyl each having up to 4
carbon atoms, fluorine, chlorine, bromine, nitro, cyano,
trifluoromethyl or straight-chain or branched alkyl having up to 4

-98-
carbon atoms, which for its part can be substituted by hydroxyl,
carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl
each having up to 4 carbon atoms,
and/or are substituted by a group of the formula -(CO)d- NR15R16,
in which
d denotes a number 0 or 1,
R15 and R16 are identical or different and denote hydrogen, phenyl,
benzyl or straight-chain or branched alkyl or acyl each having
up to 4 carbon atoms,
their isomeric forms and salts and their N-oxides.
3. Compounds according to claim 1 of the general formula (I), in which
R represents a radical of the formula
<IMGS>
where the 6-membered aromatic heterocycles R1 shown are optionally
substituted up to 2 times in an identical or different manner by
hydrogen, formyl, straight-chain or branched acyl, alkoxy or
alkoxycarbonyl each having up to 4 carbon atoms, methylamino,
amino, fluorine, chlorine, bromine, cyano, azido or straight-chain or

-99-
branched alkyl having up to 4 carbon atoms, which for its part can be
substituted by hydroxyl, carboxyl, amino, straight-chain or branched
acyl, alkoxy, alkoxycarbonyl, acylamino each having up to 3 carbon
atoms,
and/or are optionally substituted by a radical of the formula
<IMGS>
and the 6-membered aromatic heterocycles shown above under R1 are
substituted 1 to 3 times, in an identical or different manner by
(A) straight-chain or branched alkyl having 7 to 10 carbon atoms,
straight-chain or branched alkenyl having up to 6 carbon atoms
and one double bond,
straight-chain or branched alkinyl having up to 6 carbon atoms
and one triple bond,
where alkenyl and alkinyl have their double or triple
bond at the linkage point to the heterocycle R1,
cycloalkyloxy having 3 to 6 carbon atoms,
substituted phenyl,
where said alkyl, alkenyl, alkinyl and cycloalkyloxy radicals
for their part is optionally substituted and the phenyl radical is
compulsorily substituted by carboxyl, hydroxyl, cyano,
fluorine, chlorine, straight-chain, branched or cyclic alkyl, acyl,
acylamino, alkoxy, alkylthio, alkoxycarbonyl, each having up
to 3 carbon atoms,

-100-
by phenyl, which is optionally substituted by fluorine, chlorine,
alkyl, alkoxy each having 1 to 4 carbon atoms,
by 5- to 6-membered hetaryl, having 1 to 3 heteroatoms from
the series N, O, S, which is optionally substituted by fluorine,
chlorine, alkyl, alkoxy each having 1 to 4 carbon atoms,
and/or
by a group of the formula
NR aR b
in which
R a and R b are identical or different and denotes hydrogen or
straight-chain or branched acyl having up to 4 carbon
atoms, cyclic acyl having 3 to 6 carbon atoms, straight-
chain or branched alkyl having up to 4 carbon atoms or
cycloalkyl having 3 to 6 carbon atoms, where these are
optionally substituted by
hydroxyl, amino, monoalkylamino, dialkyl-
amino or by straight-chain or branched alkoxy,
acyl or alkoxycarbonyl each having up to 5
carbon atoms,
or
R a and R b together with the nitrogen atom form a heterocycle
of the formula

-101-
<IMGS>
and/or by a group of the formula
-OR d
in which
R d straight-chain or branched acyl having up to 3 carbon
atoms
and/or
(B) are substituted by a 5- to 6-membered heterocyclic ring, which
can beg saturated or unsaturated and contains 1 to 4 heteroatoms
from the series N, O, S and [lacuna] optionally [lacuna] by
fluorine, chlorine, phenyl, cyano, alkyl, alkoxy each having 1
to 4 carbon atoms, -NR h R i,
where

-102-
R h and R i can be identical or different and denote hydrogen,
straight-chain, branched or cyclic alkyl or acyl having
up to 3 carbon atoms
or
R h and R j together with the nitrogen atom form a radical of the
formula
<IMGS>
and/or
(C) are substituted by straight-chain or branched alkyl having up to
6 cart>an atoms, which is compulsorily substituted by one or
more of the following groups
cyano, cyclic acyl having 3 to 6 carbon atoms, alkylthio having
up to 6 carbon atoms, cyclic alkyl having 3 to 14 carbon atoms,
phenyl, which is optionally substituted by
fluorine, chlorine, alkyl having up to 4 carbon atoms or
alkoxy having up to 4 carbon atoms;
5- to 6-membered hetaryl having 1 to 3 heteroatoms from the
series N, O, S, which is optionally substituted by fluorine,

-103-
chlorine, alkyl having 1 to 4 carbon atoms or alkoxy having 1
to 4 carbon atoms,
-NR kR l, where one of the radicals R k and R l can be hydrogen
and the other or both independently of one another denote
straight-chain or branched acyl having up to 4 carbon atoms,
cyclic alkyl having 3 to 6 carbon atoms or R k and R l, together
with the nitrogen atom, form a heterocycle of the formula
<IMGS>
and/or
(D) are substituted by alkoxy having up to 4 carbon atoms, which
for its part is substituted by
hydroxyl, -NR nR o, where R n and R o can be identical or
different hydrogen or straight-chain, branched or cyclic alkyl or
acyl each having up to 4 carbon atoms or R n and R o together
with the nitrogen atom form a heterocycle of the formula

-104-
<IMG>
and/or
(E) are substituted by halogen-substituted acyl having up to 6
carbon atoms, acyloxy having up to 6 carbon atoms or
phenylthio, where the phenyl radical is optionally substituted
by fluorine, chlorine, alkyl, alkoxy each having 1 to 4 C atoms;
heteroarylthio having 5- to 6-membered hetaryl having 1 to 3
heteroatoms from the series N, O, S, which is optionally
substituted by fluorine, chlorine, straight-chain or branched
alkyl or alkoxy having 1 to 4 carbon atoms;
and/or
(F) are substituted by a radical of the formula
-SO2R q or -SOR r
where
R q and R r denote straight-chain or branched alkyl having 1 to 3
carbon atoms, cyclic alkyl having 3 to 6 carbon atoms,

-105-
phenyl, which is optionally substituted by fluorine, chlorine,
alkyl having 1 to 4 carbon atoms or alkoxy having 1 to
3 carbon atoms,
or 5- to 6-membered hetaryl having 1 to 3 heteroatoms from
the series N, O, S, which is optionally substituted by
fluorine, chlorine, straight-chain or branched alkyl
having 1 to 4 carbon atoms or alkoxy having 1 to 4
carbon atoms,
and/or
(G) are substituted by a radical -SO3H
and/or
(I) are substituted by a radical -CONR sR t,
where
R s and R t can be identical or different and denote hydrogen,
straight-chain or branched alkyl having 1 to 6 carbon
atoms or cycloalkyl having 3 to 6 carbon atoms,
where said alkyl or cycloalkyl radicals are optionally
substituted by cycloalkyl having 3 to 6 carbon atoms,
hydroxyl, amino, straight-chain or branched alkoxy,
acyl or alkoxycarbonyl each having up to 4 carbon
atoms,
phenyl, which is optionally substituted by fluorine,
chlorine, straight-chain or branched alkyl having 1 to 4

-106-
carbon atoms, cycloalkyl having 3 to 6 carbon atoms,
alkoxy having 1 to 4 carbon atoms;
or by 5- to 6-membered heterocyclyl having 1 to 3
heteroatoms from the series N, O, S, which is optionally
substituted by fluorine, chlorine, straight-chain or
branched alkyl having 1 to 4 carbon atoms, cycloalkyl
having 3 to 6 carbon atoms, alkoxy having 1 to 4
carbon atoms,
and/or
R s and R t denotes phenyl, which is optionally substituted by
fluorine, chlorine, straight-chain or branched alkyl
having 1 to 4 carbon atoms, cycloalkyl having 3 to 6
carbon atoms, alkoxy having 1 to 4 carbon atoms,
and/or
R s and R t denote 3- to 6-membered saturated heterocyclyl
having 1 to 3 heteroatoms from the series N, O, S;
which is optionally substituted by fluorine, chlorine,
straight-chain or branched alkyl having 1 to 4 carbon
atoms, cycloalkyl having 3 to 6 carbon atoms, alkoxy
having 1 to 4 carbon atoms,
and/or
R s and R t, together with the nitrogen atom, form a group of the
formula

-107-
<IMGS>
and/or
(J) are substituted by a radical of the formula -NR vR w
where
R v and R w can be identical or different and denote
hydroxymethyl, hydroxyethyl, SO2-alkyl having 1 to 4
carbon atoms, alkoxycarbonyl having up to 8 carbon
atoms, alkoxyalkyl having a total of up to 8 carbon
atoms, acyloxymethyl having up to 6 carbon atoms in
the acyl radical (preferably pivaloyloxymethyl) or the
following radicals
<IMGS>

-108-
<IMGS>
RX-O-CH(RY)-O-CO-,
<IMG>
where
R x and R y can be identical or different and [lacuna]
hydrogen or straight-chain or branched alkyl
having 1 to 4 carbon atoms,
R z [lacuna] straight-chain or branched alkyl having
up to 4 carbon atoms, cyclopropyl, cyclopentyl,
cyclohexyl or aryl and

-109-
m denotes a number 0, 1 or 2 and
or one of the radicals R v and R w can optionally be
hydrogen,
and/or
(K) are substituted by a radical of the formula -PO(OR)(OR')
where
R and R' denotes identical or different straight-chain, branched
or cyclic alkyl having up to 4 carbon atoms or phenyl or
benzyl,
R2 and R3, including the double bond, form a phenyl ring, which are
optionally substituted up to 2 times in an identical or different manner
by formyl, carboxyl, hydroxyl, amino, straight-chain or branched acyl,
alkoxy, or alkoxycarbonyl each having up to 4 carbon atoms, nitro,
cyano, fluorine, chlorine, phenyl or straight-chain or branched alkyl
having up to s carbon atoms, which for its part can be substituted by
hydroxyl, amino, carboxyl, straight-chain or branched acyl, alkoxy or
alkoxycarbonyl each having up to 3 carbon atoms,
A represents phenyl or represents tetrahydropyranyl, tetrahydrofuryl,
furyl or pyridyl, which are optionally substituted up to 2 times in an
identical or different manner by formyl, carboxyl, straight-chain or
branched acyl, alkylthio, alkyloxyacyl, alkoxy or alkoxycarbonyl each
having up to 3 carbon atoms, fluorine, chlorine, bromine, nitro, cyano,
trifluoromethyl or straight-chain or branched alkyl having up to 3
carbon atoms, which for its part can be substituted by hydroxyl,

-110-
carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl
each having up to 3 carbon atoms,
and/or are substituted by a group of the formula-(CO) d-NR15R16,
in which
d denotes a number 0 or 1,
R15 and R16 are identical or different and denote hydrogen or straight-chain
or
branched alkyl or acyl each having up to 3 carbon atoms,
and their isomeric forms and salts and their N-oxides.
4. Compounds according to claim 1 of the general formula (I), in which
R' represents a radical of the formula
<IMG>
where the abovementioned pyrimidyl radical is optionally substituted
up to 2 times in an identical or different manner by methyl, ethyl,
isopropyl, fluorine, amino, cyano, methoxy, chlorine, hydroxymethyl
or by a radical of the formula
<IMGS>

-111-
and the abovementioned pyrimidyl radical R1 is substituted 1 to 3
times in an identical or different manner by a radical of the formula
-SO2CH3 or by a radical of the formula -PO(OH)2, -PO(OMe)2,
-PO(OEt)2 or -PO(O iPr)2,
R2 and R3, including the double bond, together form a phenyl ring and
A represents phenyl, which is optionally substituted by fluorine or cyano
and their isomeric forms and salts and their N-oxides.
5. Process for the preparation of compounds of the general formula (I)
according
to claim 1, characterized in that
[A] compounds of the general formula (II)
<IMG>
in which
R1, R2 and R3 have the meaning indicated above,
are reacted with compounds of the general formula (III)
D-CH2-A (III)
in which

-112-
A has the meaning indicated above,
and
D represents triflate or halogen, preferably chlorine or bromine,
in inert solvents, optionally in the presence of a base,
or
[B] compounds of the general formula (N)
<IMG>
in which
A, R2 and R3 have the meaning indicated above,
and
L represents a radical of the formula -SnR17R18R19, ZnR20,
iodine or triflate,
in which
R17, R18 and R19 are identical or different and denote straight-
chain or branched alkyl having up to 4 carbon atoms,

-113-
and
R20 denotes halogen,
are reacted with compounds of the general formula (V)
R1-T (V)
in which
R1 has the meaning indicated above,
and
if L = SnR17R18R19 or ZnR20
T represents triflate or halogen, preferably chlorine or bromine,
and
if L = iodine or triflate
T represents a radical of the formula SnR17~R18~R19~, ZnR20~ or
BR21R22,
in which
R17~, R18~, R19~ and R20~ have the meaning of R17, R18, R19 and
R20 indicated above and are identical or different to
these,

-114-
R21 and R22 are identical or different and denote hydroxyl,
aryloxy having 6 to 10 carbon atoms or straight-chain
or branched alkyl or alkoxy each having up to 5 carbon
atoms, or together form a 5- or 6-membered carbocyclic
ring,
in a palladium-catalyzed reaction in inert solvents,
[C] amidines of the general formula (VI)
<IMG>
in which
A, R2 and R3 have the meaning indicated above,
are reacted with enamines of the general formula (VII)
<IMG>
in which
R1 represents one of the substituents indicated above of the 6-
membered aromatic heterocycle R1
and

-115-
Z represents a suitable leaving group such as dimethylamino or
hydroxyl,
and optionally the substituents shown under R1, R2, R3 and/or
A are varied or introduced according to customary methods,
preferably by reduction, oxidation, removal of protective
groups and/or by nucleophilic substitution.
6. Medicaments comprising at least one compound of the general formula (I)
according to claim 1.
7. Pharmaceutical preparations comprising a combination of at least one
compound of the general formula (I) according to claim 1 and at least one
organic nitrate or an NO donor.
8. Pharmaceutical preparations comprising a combination of at least one
compound of the general formula (I) according to claim 1 and compounds
which inhibit the breakdown of cyclic guanosine monophosphate (cGMP).
9. Use of compounds of the general formula (I) according to claim 1 for the
production of medicaments.
10. Use according to claim 9 for the production of medicaments for treating
cardiovascular diseases.
11. Use according to one of claims 9 or 10 in the production of medicaments
for
the prophylaxis and control of the sequelae of cerebral infarcts (cerebral
apoplexy) such as stroke, cerebral ischemia and craniocerebral trauma.

Description

WO 00/21954 PCT/EP99/07202
L~-~ ~~~gq
-1-
New heterocyclyl-methyl-substituted pyrazoles
The present invention relates to new heterocyclyl-methyl-substituted pyrazole
derivatives, processes for their preparation and their use as medicaments, in
particular as medicaments for the treatment of cardiovascular diseases.
It is already known that 1-benzyl-3-aryl-fused pyrazole derivatives inhibit
platelet
aggregation (cf. EP 667 345 A1).
The present invention relates to new heterocyclyl-methyl-substituted pyrazoles
of the
general formula (I)
R' R2
N ~ f~J R3 (I)
I
H2C;.~A
in which
Rl represents a 6-membered aromatic heterocycle having up to 3 nitrogen atoms,
which is optionally substituted up to 2 times in an identical or different
manner by hydrogen., formyl, carboxyl, hydroxyl, mercapto, straight-chain or
branched acyl, alkoxy, alkylthio or alkoxycarbonyl each having up to 6 carbon
atoms, nitro, cyano, azido, halogen, phenyl and/or is substituted by a group
of
the formula
_NR4R5
in which
CA 02346698 2001-04-06

WO 00/21954 PCT/EP99/07202
-2-
R4 and RS are identical or different and denote hydrogen or straight-chain or
branched acyl having up to 6 carbon atoms or straight-chain or
branched alkyl having up to 6 carbon atoms, which is optionally
substituted by cycloalkyl having 3 to 6 carbon atoms, hydroxyl, amino
$ or by straight-chain or branched alkoxy, acyl or alkoxycarbonyl each
having up to '.i carbon atoms,
or
R4 and RS, together with the nitrogen atom, form a 3- to 7-membered
saturated or partially unsaturated heterocycle, which can optionally
additionally contain an oxygen or sulfur atom or a radical of the
formula -NRE',
1$ in which
R6 denotf;s hydrogen or straight-chain or branched alkyl having up
to 4 carbon atoms,
and/or is substituted by straight-chain or branched alkyl having up to 6
carbon
atoms, which for its part can be substituted by hydroxyl, amino, halogen,
carboxyl, straight-chain or branched acyl, alkoxy, alkoxycarbonyl or
acylamino each having up to $ carbon atoms or by a radical of the formula
-OR',
2$
in which
R7 denotes strai~;ht-chain or branched acyl having up to 5 carbon atoms or
a group of the: formula -SiRgR9R~°,
in which
CA 02346698 2001-04-06

WO 00/21954 PCT/EP99/07202
_3_
Rg, R9 and R"' are identical or different and denote aryl having 6 to 10
carbon atoms or alkyl having up to 6 carbon atoms,
and/or is optionally substituted by a radical of the formula
O-CHZ O-(CH2)bCH3
, H ,
O~ 2~a O-(CH2)b,C
or S( .O)~rJR''R'3
in which
b and b' are identical or different and denote a number 0, 1, 2 or 3,
a denotes a number 1, 2 or 3,
I 5 R'' denotes hydrogen or straight-chain or branched alkyl having up
to 4 carbon atoms,
c denotes a number 1 or 2 and
R'2 and R'3 acre identical or different and denotes hydrogen or straight-
chain or branched alkyl having up to 10 carbon atoms, which is
optionally substituted by cycloalkyl having 3 to 8 carbon atoms
or by aryl having 6 to 10 carbon atoms, which for its part can
be substituted by halogen or
denote: aryl having 6 to 10 carbon atoms, which is optionally
substituted by halogen or
denote: cycloalkyl having 3 to 7 carbon atoms
CA 02346698 2001-04-06

WO 00/21954 PCT/EP99/07202
-4-
or
R'z and R' ', together with the nitrogen atom, form a 5- to 7-membered
saturated heterocycle, which can optionally contain a further
oxygen atom or a radical -NR'4,
in whiich
R'4 denotes hydrogen, straight-chain or branched alkyl
having up to 4 carbon atoms or a radical of the formula
O
\C \ O
HZ
or denotes benzyl or phenyl, where the ring systems
are optionally substituted by halogen,
and
the 6-membered aromatic heterocycle R', which contains up to 3
nitrogen atoms, is substituted 1 to 3 times in an identical or different
manner by
(A) straight-chain or branched alkyl having 7 to 20 carbon atoms,
straight-chain or branched alkenyl having up to 20 carbon atoms and 1
to 2 double bonds,
straight-chain or branched alkinyl having up to 20 carbon atoms and 1
to 2 triple bonds,
CA 02346698 2001-04-06

WO 00!21954 PCT/EP99/07202
-5-
where alkenyl and alkinyl have a double or triple bond at the
linkage point to the heterocycle R',
cycloalkoxy having 3 to 14 carbon atoms,
or optionally substituted aryl having 6 to 10 carbon atoms,
where the alkyl, alkenyl, alkinyl, cycloalkoxy and aryl radicals
mentioned for their part are optionally substituted and if aryl = phenyl
are compulsorily substituted by formyl, carboxyl, hydroxyl, mercaptyl,
nitro, cyano, azido, halogen, straight-chain, branched or cyclic alkyl,
acyl, acylamino, alkoxy, alkylthio, alkoxycarbonyl each having up to 6
carbon atoms,
by aryl having 6 to 10 carbon atoms, which is optionally substituted by
halogen, alkyl, alkoxy each having 1 to 6 carbon atoms,
by 5- to 6-membered hetaryl, having 1 to 3 heteroatoms from the
series N, O, S, SO, SO2, which is optionally substituted by halogen,
alkyl, alkoxy each having 1 to 6 carbon atoms,
and/or
by a group of the formula
-~aRb
in which
Ra and Rb are identical or different and denotes hydrogen or straight-
chain or branched acyl having up to 10 carbon atoms, cyclic
acyl having 3 to 8 carbon atoms, straight-chain or branched
alkyl having up to 10 carbon atoms or cycloalkyl having 3 to
14 carbon atoms, where these are optionally substituted by
CA 02346698 2001-04-06

WO 00/21954 PCT/EP99/07202
-6-
hydroxyl, amino, monoalkylamino, dialkylamino or by
straight-chain or branched alkoxy, acyl or
alkoxycarbonyl each having up to 5 carbon atoms,
or
Ra and Rb tol;ether with the nitrogen atom form a 3- to 7-membered
satural:ed or partially unsaturated heterocycle, which is
optionally substituted by
hydroxyl and which optionally additionally contains an
oxygen or sulfur atom or a radical of the formula -NR',
in which
R' denotes hydrogen or straight-chain or branched
alkyl having up to 4 carbon atoms,
and/or
by a group of the formula
-ORd
in which
Rd denotes straight-chain or branched acyl having up to 5 carbon
atoms or a group of the formula -SiReRfRg,
in which
CA 02346698 2001-04-06

WO 00/21954 PCT/EP99/07202
Re, Rf and Rg are identical or different and denote aryl having
6 to 10 carbon atoms or alkyl having up to 6 carbon
atoms,
and/or
(B) is substituted by a 3- to 14-membered heterocyclic ring, which can be
saturated or unsaturated and contains 1 to 4 heteroatoms from the
series N, O, ~>, SO, SOZ and optionally by
halogen, phenyl, cyano, alkyl, alkoxy each having 1 to 6 carbon atoms,
_NRhR~,
where
Rh and R' ca:n be identical or different and denote hydrogen, straight-
chain" branched or cyclic alkyl or acyl having up to 6 carbon
atoms
or
R" and R' together with the nitrogen atom form a 3- to 7-membered
saturated or partially unsaturated heterocycle, which optionally
additionally contains an oxygen or sulfur atom or a radical of
the fo~nmula -NR',
in which
R' denotes hydrogen or straight-chain or branched alkyl
having up to 4 carbon atoms,
and/or
CA 02346698 2001-04-06

WO 00/21954 PCT/EP99/07202
_g_
(C) is substituted by straight-chain or branched alkyl having up to 6
carbon atoms.. which is compulsorily substituted by one or more of the
following groups
formyl, merc,aptyl, nitro, cyano, cyclic acyl having 3 to 14 carbon
atoms, straight-chain or branched acyl having 6 to 14 carbon atoms,
alkoxy having; 6 to 14 carbon atoms, acylamino having 6 to 14 carbon
atoms, alkoxycarbonyl having 6 to 14 carbon atoms, alkylthio having
up to 14 carbon atoms, cyclic alkyl having 3 to 14 carbon atoms,
phenyl, which is optionally substituted by
halogen, alkyl having up to 6 carbon atoms or alkoxy having
up to ti carbon atoms;
5- to 6-membered hetaryl having 1 to 3 heteroatoms from the series N,
O, S, SO, SC>Z, which is optionally substituted by halogen, alkyl
having up to 6 carbon atoms or alkoxy having up to 6 carbon atoms;
-NRkR~, where one of the radicals Rk and R' can be hydrogen and the
other or both. independently of one another denote straight-chain or
branched acyl having up to 10 carbon atoms, cyclic alkyl having 3 to
14 carbon atoms or Rk and R~ together with the nitrogen atom form a
3- to 7-membered saturated or partially unsaturated heterocycle, which
optionally additionally contains an oxygen or sulfur atom or a radical
of the formula -NR"',
in which
Rm denotca hydrogen or straight-chain or branched alkyl having up
to 4 carbon atoms;
and/or
CA 02346698 2001-04-06

WO 00/21954 PCT/EP99/07202
-9-
(D) is substituted by alkoxy having up to 6 carbon atoms, which for its
part is substituted,
by hydroxyl, -dVR"R°, where R" and R° can be identical or
different
hydrogen or straight-chain, branched or cyclic alkyl or acyl each
having up to 6 carbon atoms or Rn and R° together with the nitrogen
atom form a 3- to 7-membered saturated or partially unsaturated
heterocycle, which optionally additionally contains an oxygen or
sulfur atom or a radical of the formula -NRp,
in which
Rp denotc;s hydrogen or straight-chain or branched alkyl having up
to 4 carbon atoms,
and/or
(E) is substituted by halogen-substituted acyl having up to 14 carbon
atoms, acylo~;y having up to 14 carbon atoms, arylthio having 6 to 10
carbon atoms, where the aryl radical is optionally substituted by
halogen, alkyl, alkoxyl each having 1 to 6 carbon atoms;
heteroarylthio, by S- to 6-membered hetaryl having 1 to 3 heteroatoms
from the series N, O, S, SO, SO2, which is optionally substituted by
halogen, straight-chain or branched alkyl or alkoxy having 1 to 6
carbon atoms,
and/or
(F) is substituted by a radical of the formula
-SOzR'~ or -SORT,
CA 02346698 2001-04-06

WO 00/21954 PCT/EP99/07202
- 10-
where
Rq and R~ denote straight-chain or branched alkyl having I to 10
carbon atoms, cyclic alkyl having 3 to 14 carbon atoms,
aryl having 6 to 10 carbon atoms, which is optionally substituted by
halogen, alkyl having 1 to 6 carbon atoms or alkoxy having 1
to 6 c~~rbon atoms,
or 5- to 6-me~mbered hetaryl having 1 to 3 heteroatoms from the series
N, O, S, SO, SO2, which is optionally substituted by
halogf;n, straight-chain or branched alkyl having 1 to 4 carbon
atoms or alkoxy having I to 4 carbon atoms,
and/or
(G) is substituted by a radical -S03H
and/or
(H) is substituted by a radical -CON=C(NHZ)Z or -C=NH(NHZ)
andlor
{I) is substituted by a radical -CONRSR'
where
RS and R' can be identical or different and denote hydrogen, straight-
chain or branched alkyl having 1 to 14 carbon atoms or
cycloalkyl having 3 to 14 carbon atoms,
CA 02346698 2001-04-06

WO 00/21954 PCT/EP99/07202
-11-
where said alkyl or cycloalkyl radicals are optionally
substituted by cycloalkyl having 3 to 6 carbon atoms, hydroxyl,
amino, straight-chain or branched alkoxy, acyl or
alkoxycarbonyl each having up to 6 carbon atoms,
aryl having 6 to 10 carbon atoms, which is optionally
substiouted by halogen, straight-chain or branched alkyl having
1 to 6 carbon atoms, cycloalkyl having 3 to 14 carbon atoms,
alkoxy having I to 6 carbon atoms,
or S- to fi-membered heterocyclyl having 1 to 3 heteroatoms
from the series N, O, S, SO, SOZ, which is optionally
substituted by halogen, straight-chain or branched alkyl having
1 to fi carbon atoms, cycloalkyl having 3 to 14 carbon atoms,
1 S alkoxy having 1 to 6 carbon atoms,
and/or
RS and Rt denote aryl having 6 to 10 carbon atoms, which is optionally
substituted by halogen, straight-chain or branched alkyl having
I to 6 carbon atoms, cycloalkyl having 3 to 14 carbon atoms,
alkox:y having 1 to 6 carbon atoms,
and/or
RS and Rt denote 3- to 10-membered saturated, partially unsaturated or
completely unsaturated heterocyclyl having 1 to S heteroatoms
from the series N, O, S; SO, SO2, which is optionally
substituted by halogen, straight-chain or branched alkyl having
1 to E> carbon atoms, cycloalkyl having 3 to 14 carbon atoms,
alkoxy having 1 to 6 carbon atoms,
andlor
CA 02346698 2001-04-06

WO 00/21954 PCT/EP99/07202
-12-
RS and R', together with the nitrogen atom, form a 3- to 7-membered
saturated or partially unsaturated heterocycle, which optionally
additionally contains an oxygen or sulfur atom or a radical of
the formula -NR~,
where
R° denotes hydrogen or a straight-chain or branched alkyl
having up to 4 carbon atoms,
and/or
(J) is substituted by a radical of the formula -NR"RW,
where
R" and RW c:an be identical or different and denote straight-chain or
branched acyl having 7 to 14 carbon atoms, cyclic acyl having
3 to E~ carbon atoms, -SOZ-alkyl having 1 to 4 carbon atoms,
hydroxymethyl, hydroxyethyl, alkoxycarbonyl having up to 5
carbon atoms, alkoxyalkyl having a total of up to 8 carbon
atoms, acyloxymethyl having up to 6 carbon atoms in the acyl
radical (preferably pivaloyloxymethyl) or the following
radicals
O
'~--O
O O ~ RX O O
O
CA 02346698 2001-04-06

WO 00/21954 PCT/EP99/07202
-13-
O OH Rx Rr O
w
I ~ v w
Ry i ,
~Rx Rv / Rx
O~RZ ,
O
Rx02C O ~ Rx R'' O
HO O
HO ,
OH O
O
RXOZC
HO O O N
HO
OH ~ I /
RX-O-CH(Ry)-O-CO- ,
(Rx~r
in whiich
RX and RY are identical or different and denote hydrogen or
straight-chain or branched alkyl having up to 4 carbon
atoms,
m denotes a number 0, 1 or 2 and
RZ denotes straight-chain or branched alkyl having up to 6
carbon atoms or cycloalkyl having 3 to 8 carbon atoms,
CA 02346698 2001-04-06

WO 00/21954 PCT/EP99/07202
- 14-
or one of the radicals R~ and RW can optionally be hydrogen,
and/or
(K) is substituted by a radical of the formula -PO(OR)(OR')
where
R and R' dc,note identical or different straight-chain, branched or
cyclic alkyl having up to 8 carbon atoms or aryl having 6 to 10
carbon atoms or benzyl,
RZ and R3, including the double bond, form a phenyl ring, which are optionally
substituted up to 3 times in an identical or different manner by formyl,
mercaptyl, carboxyl, hydroxyl, amino, straight-chain or branched acyl,
alkylthio, alkoxy, alkoxycarbonyl each having up to 6 carbon atoms, vitro,
cyano, azido, halogen, phenyl or straight-chain or branched alkyl having up to
6 carbon atoms, which for its part can be substituted by hydroxyl, amino,
carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl each
having up to S carbon atoms, or are optionally substituted by a group of the
formula -S(O)~~NR'''I~'3', in which c', R''' and R'3' have the meaning of c,
R'z and R'3 indicated above and are identical or different to these,
A represents phenyl or a 5- to 6-membered aromatic or saturated heterocycle
having up to 3 heteroatoms from the series S, N and/or O, which is optionally
substituted up to 3 times in an identical or different manner by mercaptyl,
hydroxyl, formyl, carboxyl, straight-chain or branched acyl, alkylthio,
alkyloxyacyl, alkoxy or alkoxycarbonyl each having up to 6 carbon atoms,
vitro, cyano, trifluoromethyl, azido, halogen, phenyl or straight-chain or
branched alkyl having up to 6 carbon atoms, which for its part can be
substituted by hydroxyl, carboxyl, straight-chain or branched acyl, alkoxy or
alkoxycarbonyl each having up to 5 carbon atoms,
CA 02346698 2001-04-06

WO 00/21954 PCT/EP99/07202
-15-
and/or is substituted by a group of the formula -(CO)d-NR'SR'6,
in which
S d denotes a number 0 o~r 1,
R'S and R'6 are identical or different and denote hydrogen, phenyl, benzyl or
straight-
chain or branched alls:yl or acyl each having up to 5 carbon atoms,
their isomeric forms and salts and their N-oxides.
The compounds of the general formula (I) according to the invention can also
be
present in the form of their ;salts. In general, salts with organic or
inorganic bases or
acids may be mentioned here.
In the context of the present: invention, physiologically acceptable salts are
preferred.
Physiologically acceptable salts of the compounds according to the invention
can be
salts of the substances according to the invention with mineral acids,
carboxylic acids
or sulfonic acids. Particularly preferred salts are, for example, those with
hydrochloric
acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid,
ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid,
naphthalenedisulfonic
acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid,
fumaric acid,
malefic acid or benzoic acid.
Physiologically acceptable salts can likewise be metal or ammonium salts of
the
compounds according to the invention which have a free carboxyl group. Those
particularly preferred are, for example, sodium, potassium, magnesium or
calcium salts,
and also ammonium salts which are derived from ammonia, or organic amines such
as,
for example, ethylaminc:, di- or triethylamine, di- or triethanolamine,
dicyclohexylamine, dimethylaminoethanol, arginine, lysine or ethylenediamine.
CA 02346698 2001-04-06

WO 00/21954 PCT/EP99/07202
-16-
The compounds according to the invention can exist in stereoisomeric forms
which
either behave as image and minor image (enantiomers), or which do not behave
as
image and mirror image (diastereomers). The invention relates both to the
enantiomers
or diastereomers and to their respective mixtures. Like the diastereomers, the
racemic
forms can be separated into the stereoisomerically uniform constituents in a
known
manner.
In the context of the present: invention, the substituents in general have the
following
meaning:
Alkyl having up to 20 carbon atoms in general represents, depending on the
abovementioned substituerits, a straight-chain or branched hydrocarbon radical
having 1 to 20 carbon atoms. Examples which may be mentioned are methyl,
ethyl,
propyl, isopropyl, butyl, isolbutyl, pentyl, isopentyl, hexyl, isohexyl,
heptyl, isoheptyl,
octyl and isooctyl, nonyl, decyl, dodeyl, eicosyl.
Al~ kenyl having up to 20 carbon atoms in general represents, depending on the
abovementioned substituents, a straight-chain or branched hydrocarbon radical
having 2 to 20 carbon atoms and one or more, preferably having one or two
double
bonds. Examples which many be mentioned are allyl, propenyl, isopropenyl,
butenyl,
isobutenyl, pentenyl, isopentenyl, hexenyl, isohexenyl, heptenyl, isoheptenyl,
octenyl,
isooctenyl.
Alkin 1 in general represents, depending on the abovementioned substituents, a
straight-chain or branched hydrocarbon radical having 2 to 20 carbon atoms and
one
or more, preferably having one or two triple bonds. Examples which may be
mentioned are ethinyl, 2-butinyl, 2-pentinyl and 2-hexinyl.
Acvl having up to 10 carbon atoms in general represents, depending on the
abovementioned substituents, straight-chain or branched lower alkyl having 1
to 9
carbon atoms which are bonded via a carbonyl group. Examples which may be
CA 02346698 2001-04-06

WO 00/21954 PCT/EP99/07202
-17-
mentioned are: acetyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl,
butylcarbonyl and isobutylc~~rbonyl.
A- lkoxy in general represents, depending on the abovementioned substituents,
a
straight-chain or branched hydrocarbon radical having 1 to 14 carbon atoms
bonded
via an oxygen atom. Examples which may be mentioned are methoxy, ethoxy,
propoxy, isopropoxy, butoxy, isobutoxy, pentoxy isopentoxy, hexoxy, isohexoxy,
heptoxy, isoheptoxy, octox;y or isooctoxy. The terms "alkoxy" and "alkyloxy"
are
used synonymously.
Alkoxycarbonyl can be represented, for example, by the formula
II Uakyl
C~
Alkyl in this case represents a straight-chain or branched hydrocarbon radical
having
1 to 13 carbon atoms. Examples which may be mentioned are the following
alkoxycarbonyl radicals: rr~ethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
iso-
propoxycarbonyl, butoxycarbonyl or isobutoxycarbonyl.
Cycloalkyl in general represents a cyclic hydrocarbon radical having 3 to 8
carbon
atoms. Cyclopropyl, cyclopentyl and cyclohexyl are preferred. Examples which
may
be mentioned are cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
Air 1 in general represents an aromatic radical having 6 to 10 carbon atoms.
Preferred
aryl radicals are phenyl and naphthyl.
Halogen in the context of the invention represents fluorine, chlorine, bromine
and
iodine.
Aromatic. saturated and unsaturated heterocycles in the context of the
invention,
depending on the abovementioned substituents, in general represent a 3- to 10-
CA 02346698 2001-04-06

WO 00/21954 PCT/EP99/07202
-18-
membered or 5- to 6-membc:red heterocycle which contain up to 4 heteroatoms
from
the series S, N and/or O and which can optionally also be bonded via a
nitrogen
atom. Examples which may be mentioned are: pyridyl, thienyl, furyl, pyrrolyl,
pyrrolidinyl, piperazinyl, pyrimidyl, thiazolyl, oxazolyl, imidazolyl,
tetrazolyl,
morpholinyl or piperidyl. Hc;taryl represents an aromatic heterocyclic
radical.
Cycloalkoxy in the context of the invention represents an alkoxy radical whose
hydrocarbon radical is a cyc:loalkyl radical. The cycloalkyl radical in
general has up
to 8 carbon atoms. Examples which may be mentioned are: cyclopropyloxy and
cyclohexyloxy. 'the terms "cycloalkoxy" and "cycloalkyloxy" are used
synonymously.
Preferred compounds according to the invention are those of the general
formula (I),
in which
R' represents a radical of the formula
\ N ~~ N N~ N\
or
y . ..J
N , ~ , N
which are optionally substituted up to 2 times in an identical or different
manner by hydrogen, formyl, carboxyl, hydroxyl, straight-chain or branched
acyl, alkoxy or alkoxycarbonyl each having up to 5 carbon atoms, nitro,
cyano, azido, fluorine, chlorine, bromine, phenyl and/or by a group of the
formula -NR4R5,
in which
R4 and RS are identical or different and denote hydrogen or straight-chain or
branched ac.yl having up to 4 carbon atoms or straight-chain or
CA 02346698 2001-04-06

WO 00/21954 PCT/EP99/07202
- 19-
branched alkyl having up to 4 carbon atoms, which is optionally
substituted by hydroxyl, amino or by straight-chain or branched alkoxy
having up to 3 carbon atoms, or
f
R4 and RS together with the nitrogen atom form a morpholine ring or a radical
of the formula
_ U _CH3
and/or are substituted by straight-chain or branched alkyl having up to 5
carbon atoms, which for its part can be substituted by hydroxyl, amino,
fluorine, carboxyl, straight-chain or branched acyl, alkoxy, alkoxycarbonyl or
acylamino each haring up to 4 carbon atoms or by a radical of the
formula-OR7,
in which
R' denotes straight-chain or branched acyl having up to 4 carbon atoms,
and/or optionally are substituted by a radical of the formula
O-CH2 O-(CHZ)bCH3
IChI ~ N. "
' O-(CHZ)b,CH3 OR
in which
b and b' are identical) or different and denote a number 0, l, 2 or 3,
a denotes a number 1, 2 or 3,
CA 02346698 2001-04-06

WO 00/21954 PCT/EP99/07202
-20-
R" denotes hydrogen or straight-chain or branched alkyl having up to 3
carbon atoms,
and the 6-membered aromatic heterocycles mentioned above under R1 are
substituted 1 to 3 times in an identical or different manner by
(A) straight-chain or branched alkyl having 7 to 14 carbon atoms,
straight-chain or branched alkenyl having up to 14 carbon atoms
having a double bond,
straight-chain or branched alkinyl having up to 14 carbon atoms and a
triple bond,
where alkenyl and alkinyl have a double or triple bond at the
linkage point to the heterocycle R',
cycloalkyloxy having 3 to 8 carbon atoms,
or substituted phenyl,
where said alkyl, alkenyl, alkinyl and cycloalkyloxy radicals for their
part are optionally substituted and the phenyl radical is compulsorily
substituted by carboxyl, hydroxyl, mercaptyl, nitro, cyano, azido,
fluorine, chlorine, bromine, straight-chain, branched or cyclic alkyl,
acyl, acylamino, alkoxy, alkylthio, alkoxycarbonyl, each having up to
6 carbon atoms,
by aryl havin;; 6 to 10 carbon atoms, which is optionally substituted by
fluorine, chlorine, bromine, alkyl, alkoxy each having 1 to 6 carbon
atoms,
by 5- to 6-membered hetaryl, having 1 to 3 heteroatoms from the
series N, U, S, which is optionally substituted by fluorine, chlorine,
bromine, alkyl, alkoxy each having 1 to 6 carbon atoms,
and/or
CA 02346698 2001-04-06

WO 00/21954 PCT/EP99/07202
-21 -
by a group of the formula
_NRaRb
in which
Ra and Rb are identical or different and denotes hydrogen or straight-
chain or branched acyl having up to 6 carbon atoms, cyclic acyl
having 3 to 6 carbon atoms, straight-chain or branched alkyl
having up to 6 carbon atoms or cycloalkyl having 3 to 8 carbon
atoms., where these are optionally substituted by
hydro;tyl, amino, monoalkylamino, dialkylamino or by
1 S straight-chain or branched alkoxy, acyl or alkoxycarbonyl each
having; up to 4 carbon atoms,
or
Ra and Rb together with the nitrogen atom form a 3- to 7-membered
saturated heterocycle,
which optionally additionally contains an oxygen or sulfur
atom or a radical of the formula -NR',
in which
R' denotes hydrogen or straight-chain or branched alkyl
having up to 3 carbon atoms,
and/or by a group of the formula
CA 02346698 2001-04-06

WO 00/21954 PCT/EP99/07202
-22-
-ORd
in which
Rd denotes straight-chain or branched acyl having up to 4 carbon
atoms,
and/or
(B) are substituted by a 3- to 8-membered heterocyclic ring, which can be
saturated or unsaturated and contains 1 to 4 heteroatoms from the
series N, O, ~~ and optionally by
fluorine, chlorine, bromine, phenyl, cyano, alkyl, alkoxy each having 1
to 6 carbon atoms, -NRhR',
where
R'' and R' can be identical or different and denote hydrogen, straight
chain, branched or cyclic alkyl or acyl having up to 4 carbon
atoms
or
Rh and R', together with the nitrogen atom, form a 3- to 7-membered
saturated heterocycle, which optionally additionally contains
an oxygen or sulfur atom or a radical of the formula -NR',
in which
R' denotes hydrogen or straight-chain or branched alkyl
having up to 4 carbon atoms,
CA 02346698 2001-04-06

WO 00/21954 PCT/EP99/07202
- 23 -
and/or
(C) are substituted by straight-chain or branched alkyl having up to 6
carbon atoms, which is compulsorily substituted by one or more of the
following groups
mercaptyl, nitro, cyano, cyclic acyl having 3 to 8 carbon atoms,
straight-chain or branched acyl having 6 to 10 carbon atoms, alkoxy
having 6 to 10 carbon atoms, acylamino having 6 to 10 carbon atoms,
alkoxycarbonyl having 6 to 10 carbon atoms, alkylthio having up to 10
carbon atoms, cyclic alkyl having 3 to 8 carbon atoms,
phenyl, which is optionally substituted by
fluorine, chlorine, bromine, alkyl having up to 6 carbon atoms
or alkoxy having up to 6 carbon atoms;
5- to 6-membered hetaryl having 1 to 3 heteroatoms from the series N,
O, S, which is optionally substituted by fluorine, chlorine, bromine,
alkyl having up to 6 carbon atoms or alkoxy having 1 to 6 carbon
atoms;
-NRkR~, where one of the radicals Rk and R' can be hydrogen and the
other or both independently of one another denote straight-chain or
branched acyl having up to 6 carbon atoms, cyclic alkyl having 3 to 8
carbon atoms or Rk and R~, together with the nitrogen atom, form a 3-
to 7-membered saturated heterocycle, which optionally additionally
contains an oxygen or sulfur atom or a radical of the formula -NR"',
in which
R"' denotes hydrogen or straight-chain or branched alkyl having up
to 4 carbon atoms,
and/or
CA 02346698 2001-04-06

WO 00/21954 PCT/EP99/07202
-24-
(D) are substituted by alkoxy having up to 6 carbon atoms, which for its
part is substii:uted by
S hydroxyl, -NR"R°, where R" and R° can be identical or
different
hydrogen or straight-chain, branched or cyclic alkyl or acyl each
having up to 5 carbon atoms or R" and R° together with the nitrogen
atom form a 3- to 7-membered saturated heterocycle, which optionally
additionally contains an oxygen or sulfur atom or a radical of the
I 0 formula -NRP,
in which
Rp denotes hydrogen or straight-chain or branched alkyl having up
15 to 3 carbon atoms,
and/or
(E) are substituted by halogen-substituted acyl having up to 10 carbon
20 atoms, acyloxy having up to 10 carbon atoms, arylthio having 6 to 10
carbon atoms, where the aryl radical is optionally substituted by
fluorine, chlorine, bromine, alkyl, alkoxyl each having 1 to 6 carbon
atoms, heteroarylthio, by 5- to 6-membered hetaryl having 1 to 3
heteroatoms :from the series N, O or S, which is optionally substituted
25 by fluorine, chlorine, bromine, straight-chain or branched alkyl or
alkoxy havin;; 1 to 6 carbon atoms,
and/or
30 (F) are substituted by a radical of the formula
-SOZF;q or -SOR',
CA 02346698 2001-04-06

WO 00/21954 PCT/EP99/07202
-25-
where
Rq and R~ denote straight-chain or branched alkyl having 1 to 6 carbon
atoms, cyclic alkyl having 3 to 8 carbon atoms,
aryl having i5 to 10 carbon atoms, which is optionally substituted by
fluorine, chlorine, bromine, alkyl having 1 to 6 carbon atoms
or alli;oxy having 1 to 6 carbon atoms,
or 5- to 6-mc;mbered hetaryl having 1 to 3 heteroatoms from the series
N, O, S, which is optionally substituted by
fluorine, chlorine, bromine, straight-chain or branched alkyl
having 1 to 4 carbon atoms or alkoxy having 1 to 4 carbon
atoms,
and/or
(G) are substituted by a radical -SO~H
and/or
(I) are substitutf:d by a radical -CONRSR'
where
RS and R' can be identical or different and denote hydrogen, straight-
chain or branched alkyl having 1 to 10 carbon atoms or
cycloalkyl having 3 to 8 carbon atoms,
where said alkyl or cycloalkyl radicals are optionally
substituted by cycloalkyl having 3 to 6 carbon atoms, hydroxyl,
CA 02346698 2001-04-06

WO 00/21954 PCT/EP99/07202
-26-
amino. straight-chain or branched alkoxy, acyl or
alkoxycarbonyl each having up to 5 carbon atoms,
aryl having 6 to 10 carbon atoms, which is optionally
substituted by fluorine, chlorine, bromine, straight-chain or
branched alkyl having 1 to 5 carbon atoms, cycloalkyl having 3
to 8 carbon atoms, alkoxy having 1 to 6 carbon atoms;
or 5- to 6-membered heterocyclyl having 1 to 3 heteroatoms
from the series N, O, S, which is optionally substituted by
fluorine, chlorine, bromine, straight-chain or branched alkyl
having 1 to 6 carbon atoms, cycloalkyl having 3 to 8 carbon
atoms, alkoxy having 1 to 6 carbon atoms,
and/or
RS and Rt denote aryl having 6 to 10 carbon atoms, which is optionally
substituted by fluorine, chlorine, bromine, straight-chain or
branched alkyl having 1 to 6 carbon atoms, cycloalkyl having 3
to 8 carbon atoms, alkoxy having 1 to 6 carbon atoms,
and/or
RS and Rt denote 3- to 8-membered saturated heterocyclyl having 1 to
3 heteroatoms from the series N, O, S; which is optionally
substituted by fluorine, chlorine, bromine, straight-chain or
branched alkyl having 1 to 6 carbon atoms, cycloalkyl having 3
to 8 carbon atoms, alkoxy having 1 to 6 carbon atoms,
and/or
CA 02346698 2001-04-06

WO 00/21954 PCT/EP99/07202
-27-
RS and R' together with the nitrogen atom form a 3- to 7-membered
saturated heterocycle, which optionally additionally contains
an oxygen or sulfur atom or a radical of the formula -NR",
where
R" denotes hydrogen or a straight-chain or branched alkyl
having up to 4 carbon atoms,
(J) are substituted by a radical of the formula -NR~RW
where
R~ and R'" can be identical or different and denote straight-chain or
branched acyl having 7 to 10 carbon atoms, cyclic acyl having
3 to 5 carbon atoms, -SOZ-alkyl having 1 to 4 carbon atoms,
hydroxymethyl, hydroxyethyl, alkoxycarbonyl having up to 5
carbon atoms, alkoxyalkyl having a total of up to 8 carbon
atoms, acyloxymethyl having up to 6 carbon atoms in the acyl
radic;~l (preferably pivaloyloxymethyl) or the following
radicals
O ~ O
~?--O I'
O / O ~ Rx~O O
O
O OH Rx Rv O
'a
I ~ v w
Ry I ,
~Rx , Rv ~ Rx
O I I RZ
O
CA 02346698 2001-04-06

WO 00/21954 PCT/EP99/07202
-28-
RxO2C O R" RY O
HO O
HO ,
OH O
RX02C
HO O O
HO ,
OH
RX-O-CH(RY)-O-CO- ,
(Rx~r
in which
RX and RY are identical or different and denote hydrogen or
straight-chain or branched alkyl having up to 3 carbon
atoms
m denotes a number 0, 1 or 2 and
RZ denotes straight-chain or branched alkyl having up to 4
carbon atoms, cyclopropyl, cyclopentyl or cyclohexyl,
or one of the radicals R~ and RW can optionally be hydrogen,
(K) are substituted by a radical of the formula -PO(OR)(OR')
where
CA 02346698 2001-04-06

WO 00/21954 PCT/EP99/07202
-29-
R and R' df:notes identical or different straight-chain, branched or
cyclic alkyl having up to 6 carbon atoms or aryl having 6 to 10
carbon atoms or benzyl,
RZ and R3, including the double bond, form a phenyl ring, which are optionally
substituted up to 3 times in an identical or different manner by formyl,
carboxyl, hydroxyl, amino, straight-chain or branched acyl, alkoxy, or
alkoxycarbonyl each having up to 5 carbon atoms, nitro, cyano, azido,
fluorine, chlorine, bromine, phenyl or straight-chain or branched alkyl having
up to 5 carbon atoms, which for its part can be substituted by hydroxyl,
amino, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl
each having up to 4 carbon atoms,
A represents phenyl or represents tetrahydropyranyl, furyl, tetrahydrofuryl,
morpholinyl, pyrimidyl, piperazinyl or pyridyl, which is optionally
substituted
up to 2 times in an identical or different manner by hydroxyl, formyl,
carboxyl, straight-chain or branched acyl, alkylthio, alkyloxyacyl, alkoxy or
alkoxycarbonyl each having up to 4 carbon atoms, fluorine, chlorine,
bromine, nitro, cyano, trifluoromethyl or straight-chain or branched alkyl
having up to 4 carbon atoms, which for its part can be substituted by
hydroxyl, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl
each having up to 4 carbon atoms,
and/or are substituted by a group of the formula-(CO)d-NR~SR~6,
in which
d denotes a number 0 or l,
CA 02346698 2001-04-06

WO 00/21954 PCT/EP99/07202
-30-
R'S and R'f' are identical or different and denote hydrogen, phenyl, benzyl or
straight-chain or branched alkyl or acyl each having up to 4 carbon
atoms,
their isomeric forms and salts and their N-oxides.
Particularly preferred compounds of the general formula (I) according to the
invention are those in which
R' represents a radical of the formula
N
N~.N w
or
NJ , ~-
where the 6-membe;red aromatic heterocycles R1 shown are optionally
substituted up to 2 times in an identical or different manner by hydrogen,
formyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl each having
up to 4 carbon atoms, methylamino, amino, fluorine, chlorine, bromine,
cyano, azido or straight-chain or branched alkyl having up to 4 carbon atoms,
which for its part can be substituted by hydroxyl, carboxyl, amino, straight-
chain or branched acyl, alkoxy, alkoxycarbonyl, acylamino each having up to
3 carbon atoms,
and/or are optionally substituted by a radical of the formula
-N N-CH3 , -N NH - O , - ~ or ~N~
~ OH
CA 02346698 2001-04-06

WO 00/21954 PCT/EP99/07202
-31
and the 6-member~ed aromatic heterocycles shown above under R' are
substituted 1 to 3 times, in an identical or different manner by
(A) straight-chain or branched alkyl having 7 to 10 carbon atoms.
straight-chain or branched alkenyl having up to 6 carbon atoms and
one double bond,
straight-chain or branched alkinyl having up to 6 carbon atoms and
one triple bond,
where alkenyl and alkinyl have their double or triple bond at
the linkage point to the heterocycle R',
cycloalkyloxy having 3 to 6 carbon atoms,
substituted phenyl,
where said alkyl, alkenyl, alkinyl and cycloalkyloxy radicals for their
part is optionally substituted and the phenyl radical is compulsorily
substituted by carboxyl, hydroxyl, cyano, fluorine, chlorine, straight-
chain, branched or cyclic alkyl, acyl, acylamino, alkoxy, alkylthio,
alkoxycarbonyl, each having up to 3 carbon atoms,
by phenyl, which is optionally substituted by fluorine, chlorine, alkyl,
alkoxy each having 1 to 4 carbon atoms,
by 5- to 6-rr~embered hetaryl, having 1 to 3 heteroatoms from the
series N, O, S, which is optionally substituted by fluorine, chlorine,
alkyl, alkoxy each having 1 to 4 carbon atoms,
and/or
by a group of the formula
-NRaRb
in which
CA 02346698 2001-04-06

WO 00/21954 PCT/EP99/07202
-32-
Ra and Rb are identical or different and denotes hydrogen or straight-
chain or branched acyl having up to 4 carbon atoms, cyclic acyl
having 3 to 6 carbon atoms, straight-chain or branched alkyl
having up to 4 carbon atoms or cycloalkyl having 3 to 6 carbon
atoms, where these are optionally substituted by
hydroxyl, amino, monoalkylamino, dialkylamino or by
straight-chain or branched alkoxy, acyl or
alkoxycarbonyl each having up to S carbon atoms,
or
Ra and Rb together with the nitrogen atom form a heterocycle
of the formula
-N O
U
-N NH
U
or
- ~ CH3
form
and/or by a group of the formula
_ pRd
in which
CA 02346698 2001-04-06

WO 00/21954 PCT/EP99/07202
-33-
Rd straight-chain or branched acyl having up to 3 carbon atoms
and/or
(B) are substituted by a 5- to 6-membered heterocyclic ring, which can be
saturated or unsaturated and contains 1 to 4 heteroatoms from the
series N, O, S and [lacuna] optionally (lacuna] by
fluorine, chllorine, phenyl, cyano, alkyl, alkoxy each having 1 to 4
carbon atoms.. -NR"R',
where
R" and R' can be identical ar different and denote hydrogen, straight-
chain, branched or cyclic alkyl or acyl having up to 3 carbon
atoms
or
R" and R' together with the nitrogen atom form a radical of the
formula
-N O
-~~ H
or
- ~~ CHs
and/or
CA 02346698 2001-04-06

WO 00/21954 PCT/EP99/07202
-34-
(C) are substituted by straight-chain or branched alkyl having up to 6
carbon atoms, which is compulsorily substituted by one or more of the
following groups
cyano, cyclic acyl having 3 to 6 carbon atoms, alkylthio having up to 6
carbon atoms, cyclic alkyl having 3 to 14 carbon atoms,
phenyl, which is optionally substituted by fluorine, chlorine, alkyl
having up to 4 carbon atoms or alkoxy having up to 4 carbon atoms;
5- to 6-membered hetaryl having 1 to 3 heteroatoms from the series N,
O, S, which is optionally substituted by fluorine, chlorine, alkyl having
I to 4 carbon atoms or alkoxy having I to 4 carbon atoms,
-NRkR~, wheo~e one of the radicals Rk and R~ can be hydrogen and the
other or both independently of one another denote straight-chain or
branched acyl having up to 4 carbon atoms, cyclic alkyl having 3 to 6
carbon atom;> or Rk and R~, together with the nitrogen atom, form a
heterocycle of the formula
-N O
-N NH
o~
_ ~~ CHs
and/or
(D) are substituted by alkoxy having up to 4 carbon atoms, which for its
part is substituted by
CA 02346698 2001-04-06

WO 00/21954 PCT/EP99/07202
-35-
hydroxyl, -I'TR"R°, where R" and R° can be identical or
different
hydrogen or straight-chain, branched or cyclic alkyl or acyl each
having up to 4 carbon atoms or R" and R° together with the nitrogen
atom form a heterocycle of the formula
-N O
-N NH
or
-N NCH3
_/
and/or
(E) are substituted by halogen-substituted acyl having up to 6 carbon
atoms, acyloxy having up to 6 carbon atoms or phenylthio, where the
phenyl radical is optionally substituted by fluorine, chlorine, alkyl,
alkoxy each having 1 to 4 C atoms; heteroarylthio having 5- to 6-
membered hetaryl having 1 to 3 heteroatoms from the series N, O, S,
which is optionally substituted by fluorine, chlorine, straight-chain or
branched alkyl or alkoxy having 1 to 4 carbon atoms;
and/or
(F) are substituted by a radical of the formula
-SOZRq or-SOR
where
CA 02346698 2001-04-06

WO 00/21954 PCT/EP99/07202
-36-
Rq and R~ denote straight-chain or branched alkyl having 1 to 3 carbon
atoms, cyclic alkyl having 3 to 6 carbon atoms,
phenyl, which is optionally substituted by fluorine, chlorine, alkyl
having 1 to 4 carbon atoms or alkoxy having 1 to 3 carbon
atoms,
or 5- to 6-me:mbered hetaryl having 1 to 3 heteroatoms from the series
N, O, S, which is optionally substituted by
fluarine, chlorine, straight-chain or branched alkyl having 1 to
4 carban atoms or alkoxy having 1 to 4 carbon atoms,
and/or
(G) are substituted by a radical -S03H
and/or
(I) are substituted by a radical -CONRSR',
where
RS and R' can be identical or different and denote hydrogen, straight-
chain or branched alkyl having 1 to 6 carbon atoms or
cycloa.lkyl having 3 to 6 carbon atoms,
where said alkyl or cycloalkyl radicals are optionally
substituted by cycloalkyl having 3 to 6 carbon atoms, hydroxyl,
amino, straight-chain or branched alkoxy, acyl or
alkoxycarbonyl each having up to 4 carbon atoms,
phenyl., which is optionally substituted by fluorine, chlorine,
straight-chain or branched alkyl having 1 to 4 carbon atoms,
CA 02346698 2001-04-06

WO 00/21954 PCT/EP99/07202
-37-
cyclo~alkyl having 3 to 6 carbon atoms, alkoxy having 1 to 4
carbon atoms;
or by S- to 6-membered heterocyclyl having 1 to 3 heteroatoms
S from the series N, O, S, which is optionally substituted by
fluorine, chlorine, straight-chain or branched alkyl having 1 to
4 carbon atoms, cycloalkyl having 3 to 6 carbon atoms, alkoxy
having 1 to 4 carbon atoms,
and/or
RS and Rt denotes phenyl, which is optionally substituted by fluorine,
chlorine, straight-chain or branched alkyl having 1 to 4 carbon
atoms, cycloalkyl having 3 to 6 carbon atoms, alkoxy having 1
to 4 carbon atoms,
and/or
RS and Rt demote 3- to 6-membered saturated heterocyclyl having 1 to
3 heteroatorns from the series N, O, S; which is optionally
substituted by fluorine, chlorine, straight-chain or branched
alkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 6
carbon atoms, alkoxy having 1 to 4 carbon atoms,
and/or
RS and R', together with the nitrogen atom, form a group of the
formula
CA 02346698 2001-04-06

WO 00/21954 PCT/EP99/07202
3$ -
-N O
._./
-N NH
or
_ ~~ CHs
and/or
(J) are substituted by a radical of the formula -NR"RW
where
R" and R"' c:an be identical or different and denote hydroxymethyl,
hydroxyethyl, SOZ-alkyl having 1 to 4 carbon atoms, alkoxy-
carbonyl having up to S carbon atoms, alkoxyalkyl having a
total of up to $ carbon atoms, acyloxymethyl having up to 6
carbon atoms in the acyl radical (preferably pivaloyloxymethyl)
or the following radicals
O~ O Ry O
~'- O
O ~~O , RX~O~O~ ,
O
O OH RX Rv O
w
w
i' Ry
~RX Ry / R"
RZ ,
O
CA 02346698 2001-04-06

WO 00/21954 PCT/EP99/0720Z
-39-
RX02C RX Rv O
HO O O
HO ,
OH O
R"02C
HO O O
HO ,
OH
RX-O-CH(Ry)-O-CO- ,
(RXO
where
S
RX an d RY can be identical or different and hydrogen or
straight-chain or branched alkyl having 1 to 4 carbon
atoms,
RZ straight-chain or branched alkyl having up to 4 carbon
atoms, cyclopropyl, cyclopentyl, cyclohexyl or aryl and
m denotes a number 0, 1 or 2 and
or one of the radicals R" and RW can optionally be hydrogen,
and/or
(K) are substituted by a radical of the formula -PO(OR)(OR')
CA 02346698 2001-04-06

WO 00/21954 PCT/EP99/07202
-40-
where
R and R' denotes identical or different straight-chain, branched or
S cyclic: alkyl having up to 4 carbon atoms or phenyl or benzyl,
RZ and R3, including the double bond, form a phenyl ring, which are optionally
substituted up to 2 times in an identical or different manner by formyl,
carboxyl, hydroxyl, .amino, straight-chain or branched acyl, alkoxy, or alkoxy-
carbonyl each having up to 4 carbon atoms, nitro, cyano, fluorine, chlorine,
phenyl or straight-chain or branched alkyl having up to 3 carbon atoms, which
for its part can be substituted by hydroxyl, amino, carboxyl, straight-chain
or
branched acyl, alkoxy or alkoxycarbonyl each having up to 3 carbon atoms,
A represents phenyl or represents tetrahydropyranyl, tetrahydrofuryl, furyl or
pyridyl, which are optionally substituted up to 2 times in an identical or
different manner by formyl, carboxyl, straight-chain or branched acyl, alkyl-
thio, alkyloxyacyl, ;~lkoxy or alkoxycarbonyl each having up to 3 carbon
atoms, fluorine, chlorine, bromine, nitro, cyano, trifluoromethyl or straight-
chain or branched alkyl having up to 3 carbon atoms, which for its part can
be substituted by hydroxyl, carboxyl, straight-chain or branched acyl, alkoxy
or alkoxycarbonyl each having up to 3 carbon atoms,
and/or are substituted by a group of the formula -(CO)d-NR' SR' 6,
in which
d denotes a number 0 or 1,
R'S and R'6 are identical or different and denote hydrogen or straight-chain
or
branched alkyl or acyl each having up to 3 carbon atoms,
CA 02346698 2001-04-06

WO 00/21954 PCT/EP99/07202
-41 -
and their isomeric forms and salts and their N-oxides.
Very particularly preferred compounds of the general formula (I) are those in
which
R' represents a radical of the formula
NI \ N
where the abovementioned pyrimidyl radical is optionally substituted up to 2
times in an identicall or different manner by methyl, ethyl, isopropyl,
fluorine,
amino, cyano, met:hoxy, chlorine, hydroxymethyl or by a radical of the
formula
- ~ or -N
U
and the abovementioned pyrimidyl radical R1 is substituted 1 to 3 times in an
identical or different manner by a radical of the formula -S02CH3 or by a
radical of the formula -PO(OH)2, -PO(OMe)2, -PO(OEt)2 or -PO(OiPr)2,
RZ and R3, including the double bond, together form a phenyl ring and
A represents phenyl, which is optionally substituted by fluorine or cyano
and their isomeric forms and salts and their N-oxides.
Moreover, a process for the preparation of the compounds of the general
formula (I)
according to the invention has been found, characterized in that
[A] compounds of the general formula (II)
CA 02346698 2001-04-06

WO 00/21954 PCT/EP99/07202
-42-
H
i
Ra N
/N (II)
R2 R'
in which
R', RZ and R3 have the meaning indicated above,
are reacted with compounds of the general formula (III)
D-CHZ-A (III)
in which
A has the meaning indicated above,
and
D represents triflate or halogen, preferably chlorine or bromine,
in inert solvents, optionally in the presence of a base,
or
[B] compounds of the general formula (IV)
CA 02346698 2001-04-06

WO 00/21954 PCTIEP99/07202
-43-
,A
IHZC
Rte' ~N%IV (IV)
in which
A, RZ and R3 have the meaning indicated above,
and
L represents a radical of the formula -SnR~~RlgR~9, ZnRz°, iodine
or
triflate,
in which
R~~, R~~ and R.~~ are identical or different and denote straight-chain or
branched alkyl having up to 4 carbon atoms,
and
RZ° denotes halogen,
are reacted with compounds of the general formula (V)
R~-T (V)
in which
Rl has the meaning indicated above,
CA 02346698 2001-04-06

WO 00/21954 PCT/EP99/07202
and
if L = SnR"R'gR'~~ or ZnRzo
T represents triflate or halogen, preferably chlorine or bromine,
and
if L = iodine or trifla.te
T represents a radical of the formula SnR"~R'g~R'9~, ZnR2°~ or
BRZ'R22,
in which
R"~, R'8~, R'9~ and Rz°~ have the meaning of R", R'8, R'9 and RZo
indicated above and are identical or different to these,
RZ' and R'Z are identical or different and denote hydroxyl, aryloxy
having 6 to 10 carbon atoms or straight-chain or branched alkyl
or alkoxy each having up to S carbon atoms, or together form a
5- or G-membered carbocyclic ring,
in a palladium-catalyzed reaction in inert solvents,
[C] amidines of the general formula (VI)
~A
R3
N
~N
R2 (VI)
~NH
H2N
CA 02346698 2001-04-06

WO 00/21954 PCT/EP99/07202
- 45 -
in which
A, RZ and R3 have the meaning indicated above,
are reacted with enarnines of the general formula (VII)
NC_ ~Z (VII)
~/R
in which
R~~ represents one of the substituents indicated above of the 6-membered
aromatic hete;rocycle R'
and
Z represents a suitable leaving group such as dimethylamino or
hydroxyl,
and optionally the substituents shown under R', R', R3 and/or A are varied or
introduced according to customary methods, preferably by reduction,
oxidation, removal of protective groups and/or by nucleophilic substitution.
The processes according to the invention can be illustrated by way of example
by the
following reaction schemes:
CA 02346698 2001-04-06

WO 00/21954 PCT/EP99/07202
-46-
[AJ and [B]
I
/ ~ ;N NaH ; Me6Snz (3eq). Pd(PPh)3)a
Br
F
[
CONHz
N~ ~ NHz
>=N
CI
Pd(PPh3)zCl2
N(CH3)2
/ N' F ~ CN
IV
S02
H N~ NH w N
2
N' F
~N
N
N \
NH2
S02
N
Suitable solvents for the individual steps of processes [A], [B] and [C] in
this context
are inert organic solvents which do not change under the reaction conditions.
CA 02346698 2001-04-06

WO 00/21954 PCT/EP99/07202
- 47 -
These include ethers, such as diethyl ether or tetrahydrofuran, DME, dioxane,
alcohols
such as methanol and ethanol, halogenohydrocarbons such as dichloromethane,
trichloromethane, tetrachloromethane, 1,2-dichloroethane, trichloroethane,
tetrachloro-
ethane, 1,2-dichloroethane or trichloroethylene, hydrocarbons such as benzene,
xylene,
S toluene, hexane, cyclohexane, or petroleum fractions, nitromethane,
dimethylform-
amide, acetone, acetonitrile or hexamethylphosphoramide. It is also possible
to employ
mixtures of the solvents. 7i etrahydrofuran, dimethylformamide, toluene,
dioxane or
dimethoxyethane is particul~~rly preferred.
Bases which can be employed for the processes according to the invention are
in
general inorganic or organic. bases. These preferably include alkali metal
hydroxides
such as sodium hydroxide or potassium hydroxide, alkaline earth metal
hydroxides
such as barium hydroxide, alkali metal carbonates such as sodium carbonate or
potassium carbonate, alkaline earth metal carbonates such as calcium
carbonate, or
alkali metal or alkaline earth metal alkoxides such as sodium or potassium
methoxide,
sodium or potassium ethoxide or potassium tent-butoxide, or organic amines
(trialkyl-
(C~-C6)amines) such as triethylamine, or heterocycles such as 1,4-diazabicyclo-
[2.2.2]octane (D~1BC0), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBL~, pyridine,
diaminopyridine, methylpiperidine or morpholine. It is also possible to employ
alkali
metals such as sodium and their hydrides such as sodium hydride as bases.
Sodium and
potassium carbonates, trieth:ylamine and sodium hydride are preferred.
The base is employed in an amount from 1 mol to 5 mol, preferably from 1 mol
to
3 mol, based on 1 mol of the compound of the general formula (II).
The reaction is in general carried out in a temperature range from 0°C
to 150°C,
preferably from +20°C to +1.10°C.
The reaction can be carried out at normal pressure, elevated pressure or at
reduced
pressure (e.g. 0.5 to 5 bar). In general, it is carried out at normal
pressure.
CA 02346698 2001-04-06

WO 00/21954 PCT/EP99/07202
-48-
Suitable acids for the cycliza.tion are in general protonic acids. These
preferably include
inorganic acids such as hydrochloric acid or sulfuric acid, or organic
carboxylic acids
having 1-6 C atoms, optionally substituted by fluorine, chlorine and/or
bromine, such
as acetic acid, trifluoroacetic acid, trichloroacetic acid or propionic acid,
or sulfonic
acids having C~-C4-alkyl radicals or aryl radicals such as methanesulfonic
acid,
ethanesulfonic acid, benzenesulfonic acid or toluenesulfonic acid.
The catalytic hydrogenation can in general be earned out by means of hydrogen
in
water or in inert organic solvents such as alcohols, ethers or
halogenohydrocarbons, or
their mixtures with catalysts such as Raney nickel, palladium, palladium on
animal
charcoal or platinum, or with hydrides or boranes in inert solvents, if
appropriate in the
presence of a catalyst.
The chlorination is in general carried out using the customary chlorinating
agents such
as PC13, PC15, POC13 or elf:mental chlorine. In the context of the invention
POC13 is
preferred.
If the radicals of the formulae -S(O)~NRi2R" and -S(O)~~NR~Z~R~3~ are to be
introduced,
the corresponding unsubstiti~ted precursors are first reacted with thionyl
chloride. In a
further step, reaction with the amines takes place in one of the
abovementioned ethers,
preferably dioxane. If c = 2, an oxidation is then carried out according to
customary
methods. The reactions are carried out in a temperature range from 0°C
to 70°C and at
normal pressure.
The nucleophilic substitutions and Vilsmeier reactions are earned out
according to
customary, published methods.
The reductions are in general carried out using reducing agents, preferably
using those
which are suitable for the reduction of carbonyl to hydroxyl compounds. In
this context,
reduction with metal hydrides or complex metal hydrides in inert solvents, if
appropriate in the presence of a trialkylborane, is particularly suitable. The
reduction is
preferably carried out using complex metal hydrides such as lithium
borohydride,
CA 02346698 2001-04-06

WO 00/21954 PCT/EP99/07202
-49-
sodium borohydride, potassium borohydride, zinc borohydride, lithium trialkyl
borohydride, diisobutylaluminum hydride or lithium aluminum hydride. The
reduction
is very particularly preferably carried out using diisobutylaluminum hydride
and
sodium borohydride.
S
The reductant is in general employed in an amount from 1 mol to 6 mol,
preferably
from 1 mol to 4 mol, based on 1 mol of the compounds to be reduced.
The reduction in general proceeds in a temperature range from -78°C to
+50°C,
preferably from -78°C to 0°C in the case of DIBAH, 0°C to
room temperature in the
- case of NaBH.~.
The reduction in general proceeds at normal pressure, but it is also possible
to work at
elevated or reduced pressure.
Suitable solvents for process [B] are, in particular: ethers, such as diethyl
ether or
tetrahydrofuran, DME, dioxane, halogenohydrocarbons such as dichloromethane,
trichloromethane, tetrachloromethane, 1,2-dichloroethane, trichloroethane,
tetra-
chloroethane, 1,2-dichloroethylene or trichloroethylene, hydrocarbons such as
benzene,
xylene, toluene, hexane, cyclohexane or petroleum fractions, nitromethane,
dimethylformamide, acetone, acetonitrile or hexamethylphosphoramide. It is
also
possible to employ mixW rea of the solvents. Tetrahydrofuran,
dimethylformamide,
toluene, dioxane or dimetho~s:yethane are particularly preferred.
The reaction is in general earned out in a temperature range from 0°C
to 150°C,
preferably from 110°C to 150°C.
The reaction can be carried out at normal pressure, elevated pressure or at
reduced
pressure (e.g. 0.5 to S bar). In general it is earned out at normal pressure.
Suitable palladium compounds in the context of the present invention are in
general
PdClz(P(C6H5)3)z, palladium bis-dibenzylideneacetone (Pd(dba)z), [1,1'-bis-
CA 02346698 2001-04-06

WO 00/21954 PCT/EP99/07202
-50-
(diphenylphosphino)ferrocene]-palladium(II) chloride (Pd(dppf)CIZ) or
Pd(P(C6H5)3)a.
Pd(P(C6H5)~)a is preferred.
The compounds of the general formula (IV) are known and can be prepared
according
to customary methods.
Process [C] is carried out i:n a temperature range from 55°C to
120°C, preferably at
80°C.
In process [C], either the fi-e;e amidine base is employed. In this case the
enamines
function as solvents. Or the amidines are reacted in the form of their salts,
preferably
hydrochlorides in the presence of a base, preferably sodium methoxide or
potassium
tert-butoxide in alcohols, preferably methanol or ten-butanol.
1 S The use of the enols is reacted in an inert solvent, preferably toluene,
with the free
amidine base.
Process [C] can be carried out at normal pressure, elevated pressure or at
reduced
pressure (e.g. 0.5 to 5 bar). In general it is earned out at normal pressure.
The amidines of the general of the formula (VI) are new and therefore a
further subject
of the invention. They cam be prepared by reacting the compounds of the
general
formula (VIII)
A1
R3 N~N
(VIII)
R2 CN
in which
A, Rz and R3 have the meaning indicated above,
with sodium methoxide to give compounds of the general formula (IX)
CA 02346698 2001-04-06

WO 00/21954 PCT/EP99/07202
-51 -
A'
R3 N~N
R2 ~NH (IX)
OMe
in which
A, RZ and R3 have the meaning indicated above,
in a next step converting these by reaction with NHaCI and glacial acetic acid
in
alcohols into the corresponding amidine HC'1 salt of the general formula (X)
A\
N~N
RZ ~NH
HzN (X)
x HCI
in which
A, R2 and R3 have the meaning indicated above,
and in a last step treating these with bases, preferably sodium carbonate.
The conversion of the nitrite into the iminoether can be earned out both in
acids,
such as using HCI/alcoho:l mixtures, and under basic conditions, such as using
methanol/sodium rnethoxide.
The preparation of the pyrinnidine is earned out according to customary
methods.
In this connection, it is possible to start both from the imino ether and to
react this,
for example, with a suitable enamine. However, the imino ether can also be
first
converted into an amidine by means of ammonia or its salts and this can be
reacted
with enamines, either as a flee base or as a salt.
CA 02346698 2001-04-06

WO 00/21954 PCT/EP99/07202
-52-
Instead of the enamine of the formula (VII), it is also possible to employ
other
aldehyde equivalents such as acetals, aminals, enol ethers, aldehydes or
enols.
S The enamines can be prepared, for example, from C-H-acidic compounds such as
acetonitrile derivatives according to known methods, by reaction with
dimethylformamide derivatives such as bis(dimethylamino)-tert-butoxymethane,
dialkoxy-dialkylamino-urethanes.
Suitable solvents for the reaction of the compounds of the general formulae
(IX)~ (X)
are alcohols such as methanol or ethanol. Methanol is preferred.
The reaction is carried out in a temperature range from 0°C to
40°C, preferably at
room temperature.
The reaction can be carried out at normal pressure, elevated pressure or at
reduced
pressure (e.g. 0.5 to 5 bar). ha general it is earned out at normal pressure.
Suitable bases for the release of the free amidine bases from the
hydrochlorides (X) are
inorganic or organic bases. 'lf hese include, for example, alkali metal
hydroxides such as
sodium hydroxide or potassium hydroxide, alkaline earth metal hydroxides such
as
barium hydroxide, alkali metal carbonates such as sodium carbonate or
potassium
carbonate, alkaline earth rr~etal carbonates such as calcium carbonate, alkali
metal
alkoxides such as potassium tent-butoxide. Sodium carbonate and potassium tert-
butoxide are preferred.
The reaction is carried out in a temperature range from 0°C to
40°C, preferably at
room temperature.
The reaction can be carried out at normal pressure, elevated pressure or at
reduced
pressure (e.g. 0.5 to S bar). In general it is carried out at normal pressure.
CA 02346698 2001-04-06

WO 00/21954 PCT/EP99/07202
-53-
The compounds of the general formula (VII) are new and can be prepared by
reacting
the compounds of the formula (XI)
(CH3)2N)' CH-O
(XI)
with compounds of the formmla (XII)
Q'-CH2 CN
(XII)
in which
Q' represents one of the substituents of RI described above,
at temperatures of 80 to 120°C.
The compounds of the general formulae (XI) and (XII) are known and can be
prepared according to customary methods.
The compounds of the general formulae (IX) and (X) are new and can be prepared
as
described above.
The compounds of the formula (VIII) can be prepared by reacting the
corresponding 3-
cyano-indazoles with compounds of the general formula (XIII)
Br~A
(XIII)
in which
A has the meaning indicated above,
CA 02346698 2001-04-06

WO 00/21954 PCT/EP99/07202
-54-
in inert solvents, preferably with tetrahydrofuran in the presence of a base,
preferably
sodium hydride.
The compounds of the general formula (XIII) are known or can be prepared
according
to customary methods.
The compounds of the general formula (I) according to the invention exhibit an
unforeseeable, valuable spectrum of pharmacological action.
The compounds of the general formula (I) according to the invention lead to
vasorelaxation, inhibition of platelet aggregation and to a blood pressure
decrease and
also to an increase in the coronary blood flow. These actions are mediated via
direct
stimulation of soluble guanyllate cyclase and an intracellular cGMP increase.
Moreover,
the compounds of the general formula (I) according to the invention intensify
the action
1 S of substances which increase the cGMP level, such as EDRF (endothelium
derived
relaxing factor), NO donors, protoporphyrin IX, arachidonic acid or
phenylhydrazine
derivatives.
They can therefore be employed in medicaments for the treatment of
cardiovascular
diseases such as for the treatment of high blood pressure and of cardiac
insufficiency,
stable and unstable angina pectoris, peripheral and cardiac vascular diseases,
of
arrhythmias, for the treatment of thromboembolic diseases and ischemias such
as
myocardial infarct, stroke, transitory and ischemic attacks, peripheral
circulatory
disorders, prevention of restenoses such as after thrombolysis therapy,
percutaneous
transluminal angioplasty (F'TA), percutaneous transluminal coronary
angioplasty
(PTCA), bypass and for the treatment of arteriosclerosis and diseases of the
urogenital
systems such as prostate hpertrophy, erectile dysfunction, female sexual
dysfunction
and incontinence.
Moreover, the invention includes the combination of the compounds of the
general
formula (I) according to the invention with organic nitrates and NO donors.
CA 02346698 2001-04-06

WO 00/21954 PCT/EP99/07202
-55-
Organic nitrates and NO donors in the context of the invention are in general
substances which display their therapeutic action by means of the release of
NO or NO
species. Sodium nitroprusside, nitroglycerin, isosorbide dinitrate, isosorbide
mononitrate, molsidomine and SIN-1 are preferred.
The invention moreover includes combination with compounds which inhibit the
breakdown of cyclic guanosine monophosphate (cGMP). These are, in particular,
inhibitors of phosphodiesterases 1, 2 and 5; nomenclature according to Beavo
and
Reifsnyder ( 1990) TIPS 11 hp. 150 to 155. By means of these inhibitors, the
action of
the compound according to the invention is potentiated and the desired
pharmacological effect is increased.
For the determination of the cardiovascular actions, the following
investigations were
earned out: In in vitro investigations on cells of vascular origin, the
influence on
guanylate cyclase-dependent cG:MP formation was tested with and without NO
donor.
The antiaggregatory properties were shown on human platelets stimulated with
collagen. The vasorelaxant action was determined on rabbit aortal rings
precontracted
using phenylephrine. The hypertensive actions were investigated on
anesthetized and
conscious rats.
Stimulation of soluble ~uanylate cyclase in primary endothelial cells
Primary endothelial cells were isolated from porcine aortas by treatment with
collagenase soln. The cells 'were then cultured in culture medium at
37°C / 5% COZ
until reaching confluence. For the investigations, the cells were passaged,
inoculated
into 24-hole cell culture plates and subcultured until reaching confluence (~
2 x 105
cells / hollow). For the stimulation of endothelial guanylate cyclase, the
culture
rmedium was aspirated and the cells were washed once with Ringer's solution.
After
removing the Ringer's solution, the cells were incubated at 37°C / S%
COZ for 10
minutes in stimulation buffer with or without NO donor (sodium nitroprusside,
SNP or
DEA/NO 1 pM). Following this, the test substances (final concentration 1 pM)
were
pipetted into the cells and incubation was continued for a further 10 minutes.
After the
CA 02346698 2001-04-06

WO 00/21954 PCT/EP99/07202
-SEi-
end of the incubation time, the buffer solution was aspirated and cold stop
buffer (4°C)
was added to the cells. The cells were then lyzed at -20°C for 16
hours. The
supernatants containing the intracellular cGMP were then removed and the cGMP
concentrations were determined by means of the cGMP-SPA system (Amersham Buch
ler, Brunswick).
Vasorelaxant action in vitro
Rabbits are stunned by a blow to the neck and exsanguinated. The aorta is
removed,
freed from adherent tissue, divided into rings 1.5 mm wide and brought
individually
under a pretension into 5 ml organ baths containing warm (37°C),
carbogen-aerated
Krebs-Henseleit solution of the following composition (mM): NaCI: 119; KCI:
4.8;
CaCl2 x 2 HZO: 1; MgSO,~ a; 7 H20; 1.4; KHZPO4: 1.2; NaHC0~:25; glucose: 10.
The
contractile force is determined using Statham UC2 cells, amplified and
digitalized by
1 S means of A!D converters (DAS-1802 HC, Keithley Instruments Munich) and
recorded
in parallel on a linear recorder. For the production of a contraction,
phenylephrine is
added to the bath cumulatively in increasing concentration. After a number of
control
cycles, the substance to be investigated is investigated in increasing dose in
each case in
each further passage and thf; height of the contraction is compared with the
height of
the contraction achieved in the last previous passage. From this, the
concentration is
calculated which is necessary in order to reduce the height of the control
value by 50%
(ICSO). The standard application volume is 5 pl and the DMSO content in the
bath
solution corresponds to 0.1 °/,.
In this remainder, the compounds of the examples show ICsp values of <10 pM.
Blood pressure measuremewts on anesthetized rats
Male Wistar rats having a body weight of 300 - 350 g are anesthetized with
thiopental
(100 mg/kg i.p.). After tracheotomy, a catheter is inserted into the femoral
artery for
blood pressure measurement. The substances to be tested are administered
orally in
Transcutol, Cremophor EL,1H20 ( 10%/20%/70%) in a volume of 1 ml/kg.
CA 02346698 2001-04-06

WO 00/21954 PCT/EP99/07202
-57-
Action on the mean blood pressure of conscious, spontaneously hypertensive
rats
Continuous blood pressure measurements over 24 hours were carried out on
spontaneously hypertensive female rats (MOL:SPRD) having freedom of movement
and weighing 200-250 g. To this end, pressure transducers (Data Sciences Inc.,
St.
Paul, MN, USA) had been implanted chronically in the animals in the descending
abdominal aorta under the renal artery and the transmitters associated
therewith had
been fixed in the abdominal cavity.
The animals were kept individually in type III cages, which were positioned at
the
individual receiver stations., and were acclimatized to a 12-hour light/dark
cycle.
Water and feed were freely available.
For determination of the data, the blood pressure of each rat was recorded for
10
seconds every 5 minutes. The measurements were in each case collected for a
period
of 15 minutes and the mean value was calculated from these values.
The test compounds were dissolved in a mixture of Transcutol (10%), Cremophor
(20%), Hz0 (70%) and administered orally in a volume of 2 ml/kg of body weight
by
means of stomach tube. The test doses were between 0.3 - 30 mg/kg of body
weight.
Inhibition of platelet a~~re~ation in vitro
For the determination of platelet aggregation, blood from healthy subjects of
both
sexes was used. As an anticoagulant, 9 parts of blood was admixed to one part
of
3.8% strength sodium citrate solution. The blood was centrifuged at 900 rpm
for
20 min. The pH of the platelet-rich plasma obtained was adjusted to pH 6.5
using
ACD solution (sodium citra.te/citric acid/glucose). The platelets were then
removed
by centrifugation and taken up in buffer and again removed by centrifugation.
The
CA 02346698 2001-04-06

WO 00/21954 PCT/EP99/07202
-58-
platelet precipitate was taken up in buffer and additionally treated with 2
mmol/I of
CaCI 2.
For the aggregation measurements, aliquots of the platelet suspension were
incubated
at 37°C for 10 min with the test substance. The aggregation was then
induced in an
aggregometer by addition of collagen and determined at 37°C by means of
the
turbidometric method according to Born (Born, G.V.R., J.Physiol. (London),
168,
178-195, 1963).
The compounds of the general formula (I) described in the present invention
are also
active compounds for the control of diseases in the central nervous system
which are
characterized by disorders of the NO/cGMP system. In particular, they are
suitable for
the elimination of cognitive deficits, for the improvement of learning and
memory
power and for the treatment of Alzheimer's disease. They are also suitable for
the
treatment of disorders of the central nervous system such as states of
anxiety, tension
and depression, sexual dysfi.~nctions and sleep disorders related to the
central nervous
system, and for the regulation of pathological disorders of food, luxury food,
drink and
tobacco and addictive agent ingestion.
Furthermore, the active compounds are also suitable for the regulation of the
cerebral
circulation and are thus efficacious agents for the control of migraine.
They are also suitable far the prophylaxis and control of the sequelae of
cerebral
infarcts (cerebral apoplexy) such as stroke, cerebral ischemia and
craniocerebral
trauma. The compounds of the general formula (I) according to the invention
can also
be employed for the control ~of painful conditions.
The present invention includes pharmaceutical preparations which, in addition
to non-
toxic, inert pharmaceutically suitable vehicles, contains the compounds of the
general
formula (I) according to the invention and to processes for the production of
these
preparations.
CA 02346698 2001-04-06

WO 00/21954 PCT/EP99/07202
_59_
The active compound can optionally also be present in microencapsulated form
in one
or more of the vehicles indicated above.
The therapeutic active compounds of the general formula (I) should be present
in the
abovementioned pharmaceutical preparations in a concentration of approximately
0.1
to 99.5, preferably of approximately 0.5 to 95% by weight, of the total
mixture.
Apart from the compounds of the general formula (I) according to the
invention, the
abovementioned pharmaceutical preparations can also contain further
pharmaceutical
active compounds.
In general, it has proven advantageous both in human and in veterinary
medicine to
administer the active compounds) according to the invention in total amounts
of
approximately 0.5 to appro:~imately 500, preferably 5 to 100, mg/kg of body
weight
every 24 hours, if appropriate in the form of several individual doses, to
achieve the
desired results. An individual dose contains the active compounds) according
to the
invention preferably in amounts from approximately 1 to approximately 80, in
particular 3 to 30, mg/kg of body weight.
CA 02346698 2001-04-06

WO 00/21954 PCT/EP99/07202
-60-
Examples
Starting compounds
Example lA
1-(2-Fluorobenzyl)-3-cyanoindazole
CN
~N
N
F
12.0 g (83.9 mmol) of 3-cy;anoindazole were dissolved in 100 ml of abs. THF
under
argon and 20.6 g ( 109 mmol) of 2-fluorobenzyl bromide were added. 2.55 g
(100 mmol) of sodium hydride (95%) were added in portions with ice-cooling.
After
stirnng overnight at room temperature, the mixture was concentrated to about a
quarter of the volume on a rotary evaporator and treated with H20 and ethyl
acetate.
The aqueous phase was again extracted with ethyl acetate. Drying of the
combined
organic phases over MgSC~4 and removal of the solvent by distillation on a
rotary
evaporator yielded the product.
Yield: 19.5 g (93%)
Rf: 0.69 (silica gel; cyclohexanelethyl acetate 1:1)
CA 02346698 2001-04-06

WO 00/21954 PCT/EP99/07202
-61 -
Example ZA
1-(2-Fluorobenzyl)indazol-:3-amidinium chloride
H2N IVH
x HCI
\ wN
I
/ VV
F
A sodium methoxide solution prepared from 190 mg (8.26 mmol) [lacuna] and 30
ml
of abs. methanol was added to a solution of 20.0 g (79.9 mmol) of 1-(2-
fluorobenzyl)-3-cyanoindazole in 200 ml of methanol and the mixture was
stirred at
40°C for 22 h. After addition of 0.46 ml of acetic acid and 4.30 g of
NH4C1, the
mixture was stirred at 40°C' for a further 24 h and then concentrated
to dryness on a
rotary evaporator. Taking the residue up in acetone and filtering off the
precipitate
residual with suction yielded the product, after drying in a high vacuum, in
the form
of a pale beige powder.
Yield: 20.5 g (84%)
M.p.: >230°C
MS-EI: m/z (%) = 268 (31, M+ of the free base), 251 (15), 109 (100).
General procedure for the preparation of 2-substituted 3-dimethylamino-
acrylonitriles
R
R~CN + ~a~~~ --.- / CN
,'N~ ,N~
50.0 mmol of 2-substituted acetonitrile derivative are added with water
cooling to a
solution of 5.95 g (50.0 mmol) of N,N-dimethylformamide dimethyl acetal in 25
ml
of abs. methanol and the mixture is stirred at room temperature for 1 h.
CA 02346698 2001-04-06

WO 00/21954 PCT/EP99/07202
-62-
Sulfones: The precipitate is filtered off with suction and dried in a high
vacuum.
Phosphonic acid esters: The solution is first freed from methanol at
40°C and
20 mbar on a rotary evaporator, then at room temperature in a
high vacuum.
Example 3A
Starting material Product Yield m.p.
\ I O ~N \ i II $$ % 128°C
N' _S~CN ~S \
II NC (I N-~
O O
Example 3B
Starting material Product Yield 'H-NMR
99%
I H-NMR (400
O N ~ MHz, CDCl3),8 =
0~~,~CN ~ ~P-O 1.34 (t, 6H, CH3),
II NC p ~ 3.12 (s, 3H, NCH3),
O 3.31 (s, 3H, NCH3),
4.07 (m, 4H, CHZ),
7.20 (d, 1 H, olefin-
CH).
CA 02346698 2001-04-06

WO 00/21954 PCT/EP99107202
-63-
Starting compound 4A
1-(2-Fluorobenzyl)-3-iodoin dazole
I
~ ~ IN
F
20.0 g (82.0 mmol) of 3-iodoindazole were dissolved in 200 ml of abs. THF
under
argon. 2.49 g (97.6 mmol) of sodium hydride (95%) [lacuna] added and stirred
at
room temperature for 45 min. After addition of 18.6 g (98.4 mmol) of 2-
fluorobenzyl
bromide and stirnng overnight at room temperature, the mixture was treated
with
ethyl acetate and sat. Na('1 solution. The organic phase was washed with
water, dried
over MgS04 and then concentrated to dryness on a rotary evaporator.
Yield: 29.0 g (100°/~, purity according to GC: 80 %)
Rf: 0.78 (silica gel; cyclohexane/ethyl acetate 1:1 )
Starting compound 5A
1-(2-Fluorobenzyl )-3-(trime;thylstannyl)indazole
Sn(CH3)s
\ \II
/ IV
F
23.6 g (67.0 mmol) of 1-(2-fluorobenzyl)-3-iodoindazole, 66.4 g of
hexamethylditin
(203 mmol) and 8.00 g of Pd(PPh3)4 were heated under reflux overnight in 680
ml of
1,4-dioxane under an argon atmosphere. The mixture, which had been cooled to
CA 02346698 2001-04-06

WO 00/21954 PCT/EP99/07202
-64-
room temperature, was extracted with 200 ml of 1 M aqueous KF solution and
with
ethyl acetate. The organic phase was dried over MgS04 and then concentrated to
dryness on a rotary evaporator. Purification was carried out in 3 portions by
chromatography on silica ge;l (cyclohexane/ethyl acetate 50:1 ).
Yield: 16.6 1; (64%, purity of the 3 batches according to GC: 79-94%,
remainder: PPh3)
Rf: 0.95 (silica gel; cyclohexanelethyl acetate 1:1)
M.p.: 71 °C
Starting compound 6A
4-Amino-2-chloropyrimidine-5-carboxamide
CONH2
NH2
N\/N
~CI
1.00 g of 2,4-dichloropyrimidine-5-carbonyl chloride (4.73 mmol) were
dissolved in
10 ml of 1,4-dioxane under argon and ammonia was passed in at 10°C for
15
minutes. After standing at room temperature for two days, the precipitate was
filtered
off with suction, washed with a little water and dried in a high vacuum.
Yield: 700 mg (86 %)
Rf: 0.06 (silica gel; cyclohexane/ethyl acetate 1:1)
MS-EI: rn/z (~%) = 172 (100, Cl, M+), 156 (71, Cl), 137 (22), 120 (28),
68 (3l.).
CA 02346698 2001-04-06

WO 00/21954 PCT/EP99/07202
- 65 -
Preparation examples
Example 1
3-[4-Amino-5-(2-pyridyl)-2-pyrimidyl]-1-(2-fluorobenzyl)indazole
350 mg (2.00 mmol) of sodium methoxide solution (30%, in methanol) were
treated
under argon with 5 ml of abs. methanol and 610 mg (2.0 mmol) of I-(2-fluoro-
benzyl)indazole-3-amidiniurn chloride. After stirring at room temperature for
5
minutes, 346 mg (6.00 mol) of 2-(2-pyridyl)-3-dimethylaminoacrylonitrile were
added and the mixture wars heated under reflux overnight. After cooling to
room
temperature, the precipitate was filtered off with suction and stirred in
pentane.
Filtering off the precipitate 'with suction again and drying it in a high
vacuum yielded
the product in the form of a pale solid.
Yield: 315 mg (40 °~o)
MS-EI: m/z (%) = 396 (100, M+), 395 (49), 301 (28), 109 (28).
CA 02346698 2001-04-06

WO 00/21954 PCT/EP99/07202
-66-
Example 2
3-[4-Amino-S-methanesulfc~nyl-2-pyrimidyl]-1-(2-fluorobenzyl)indazole
\\S.iO
NH2
1~1 AI
F
304 mg (1.00 mmol) of 1-(2-fluorobenzyl)indazole-3-amidinium chloride, 174 mg
(1.00 mmol) of 2-methanesulfonyl-3-dimethylaminoacrylonitrile (can be prepared
analogously to example 3A using 2-methanesulfonylacetonitrile as the starting
compound), 5 ml of tert-but;anol and 123 mg (1.20 mmol) of potassium tert-
butoxide
were stirred at 80°C overnight. The resulting precipitate was filtered
off with suction,
washed with water and pentane and dried in a high vacuum.
Yield: 21 S mg (54 °/>)
MS-EI: m/z (%) = 39'7 (60, M+), 302 (30), 109 ( 100).
CA 02346698 2001-04-06

WO 00/21954 PCT/EP99/07202
-67-
Example 3
3-[4-Amino-5-(2-pyridylsul fonyl)-2-pyrimidyl]-1-(2-fluorobenzyl)indazole
304 mg (1.00 mmol) of 1-(2-fluorobenzyl)indazole-3-amidinium chloride, 237 mg
( 1.00 mmol) of 2-(2-pyrielylsulfonyl)-3-dimethylaminoacrylonitrile, 5 ml of
tert-
butanol and 123 mg (1.20 mmol) of potassium tent-butoxide were stirred at
80°C
overnight. The resulting precipitate was filtered off with suction and
absorbed on
silica gel. It was possible to isolate the product by chromatography on silica
gel
(cyclohexane/ethyl acetate 2 G:1 -~ 1:1 -~ 0: I 00).
Yield: 120 mg (26 °~o)
MS-EI: m/z (%) = 460 (18, M+), 396 (47), 395 (47), 287 (30), 109 (100).
CA 02346698 2001-04-06
O
N
~~NHZ

WO 00/21954 PCT/EP99/07202
-68-
Example 4
4-Diedhylamino-2-[ 1-(2-flworobenzyl)indazol-3-yl]pyrimidine-5-phosphonate
609 mg (2.00 mmol) of I-(2-fluorobenzyl)indazole-3-amidinium chloride, 464 mg
(2.00 mmol) of diethyl 1-cyano-1-(dimethylamono)methylene-methanephosphonate
(can be prepared analogously to ex. 3b from 2-(diethoxyphosphoryl)-
acetonitrile),
ml of tert-butanol and 2466 g (2.40 mmol) of potassium tent-butoxide were
stirred
10 at 80°C overnight. The mixture was absorbed on silica gel and the
product was
isolated by chromatography on silica gel (cyclohexane/ethyl acetate 30:1 -~
1:1).
- Yield: 167 mg ( 18 °/.)
M.p.: 152°C
MS-EI: m/z (%) = 44_'i (100, M+), 109 (91).
CA 02346698 2001-04-06
O
,/

WO 00/21954 PCT/EP99/07202
-69-
Example 5
Diisopropyl 4-amino-2-[ 1-(:?-fluorobenzyl)indazol-3-yl]pyrimidine-5-
phosphonate
P
~~NH2
A1 AI
304 mg (1.00 mmol) of 1-(2-fluorobenzyl)indazole-3-amidinium chloride, 260 mg
(1.00 mmol) of diisopropyl 1-cyano-1-(dimethylamino)methylene methane
phosphonate, 5 ml of tert-butanol and 123 mg (1.20 mmol) of potassium tert
butoxide were stirred at 80°C.' overnight. The mixture was absorbed on
silica gel and
the product was isolated by chromatography on silica gel (cyclohexane/ethyl
acetate
20:1 -> 1:1 )..
Yield: 171 mg (35 °/.)
M.p.: 182°C
MS-EI: m/z (%) = 483 (44, M+), 109 ( 100).
CA 02346698 2001-04-06

WO 00/21954 PCT/EP99/07202
_70_
Example 6
4-Amino-2-[ 1-(2-fluorobenayl)indazol-3-yl)pyrimidine-S-carboxamide
638 mg (1.64 mmol) of 1-(2-fluorobenzyl)-3-(trimethylstannyl)indazole 282 mg,
(1.64 mmol) of 4-amino-2-chloropyrimidine-5-carboxamide and 69.0 mg
(0.10 mmol) of Pd(PPh3),~C12 were stirred overnight at 150°C in 17 ml
of DMF
under argon. The mixture which had been cooled to room temperature, was
treated
with water and extracted v~ith ethyl acetate. The organic phase dried over
MgS04
was absorbed on silica gel and chromatographed (cyclohexane/ethyl acetate 50:1
~ 1:l --~ 0:100), a product--containing fraction being isolated at Rf= 0.06
which was
further purified by preparative HPLC.
Yield: 42 mg (7,1 °/o)
Rf: 0.06 (silica gel; cyclohexane/ethyl acetate 1:1)
MS-EI: m/z (%) = 362 (100, M+), 267 (25), 109 (81).
CA 02346698 2001-04-06
CONH2
NHz
At AI