U.S. patent application number 10/856153 was filed with the patent office on 2004-11-11 for novel substituted pyrazole derivatives.
This patent application is currently assigned to Bayer HealthCare AG. Invention is credited to Alonso-Alija, Cristina, Dembowsky, Klaus, Feurer, Achim, Hutter, Joachim, Perzborn, Elisabeth, Stahl, Elke, Stasch, Johannes-Peter, Straub, Alexander.
Application Number | 20040224945 10/856153 |
Document ID | / |
Family ID | 7875637 |
Filed Date | 2004-11-11 |
United States Patent
Application |
20040224945 |
Kind Code |
A1 |
Straub, Alexander ; et
al. |
November 11, 2004 |
Novel substituted pyrazole derivatives
Abstract
The present invention relates to novel substituted pyrazole
derivatives of the general formula (I) 1 in which R.sup.1, R.sup.2,
R.sup.3 and A are each as defined, and to processes for their
preparation and to their use as medicaments, in particular as
medicaments for the treatment of cardiovascular disorders.
Inventors: |
Straub, Alexander;
(Wuppertal, DE) ; Feurer, Achim; (Wilhelmsfeld,
DE) ; Alonso-Alija, Cristina; (Haan, DE) ;
Stasch, Johannes-Peter; (Solingen, DE) ; Perzborn,
Elisabeth; (Wuppertal, DE) ; Hutter, Joachim;
(Wuppertal, DE) ; Dembowsky, Klaus; (Munchen,
DE) ; Stahl, Elke; (Bergisch Gladbach, DE) |
Correspondence
Address: |
JEFFREY M. GREENMAN
BAYER PHARMACEUTICALS CORPORATION
400 MORGAN LANE
WEST HAVEN
CT
06516
US
|
Assignee: |
Bayer HealthCare AG
Leverkusen
DE
|
Family ID: |
7875637 |
Appl. No.: |
10/856153 |
Filed: |
May 28, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10856153 |
May 28, 2004 |
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09744830 |
Apr 11, 2001 |
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6743798 |
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09744830 |
Apr 11, 2001 |
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PCT/EP99/05074 |
Jul 16, 1999 |
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Current U.S.
Class: |
514/227.5 ;
514/235.5; 514/254.05; 514/326; 514/365; 514/374; 514/397; 514/406;
544/140; 544/371; 544/60; 546/211; 548/205; 548/215; 548/312.4;
548/364.1 |
Current CPC
Class: |
A61P 9/12 20180101; C07D
471/04 20130101; A61P 29/00 20180101; A61P 43/00 20180101; A61P
9/00 20180101; A61P 9/10 20180101; A61P 15/08 20180101; A61P 7/02
20180101 |
Class at
Publication: |
514/227.5 ;
514/235.5; 514/254.05; 514/326; 514/365; 514/374; 514/397; 514/406;
544/060; 544/140; 544/371; 546/211; 548/205; 548/215; 548/312.4;
548/364.1 |
International
Class: |
C07D 417/02; C07D
413/02; C07D 43/02 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 29, 1998 |
DE |
198 34 044.3 |
Claims
1. A compound of the formula (I) 143in which R.sup.1 represents a
saturated or aromatic 5- or 6-membered heterocycle having up to 3
heteroatoms from the group consisting of S, N and O, which may be
attached via a nitrogen atom, and which is optionally substituted
up to 2 times by identical or different radicals from the group (i)
consisting of hydrogen, amino, azido, formyl, mercaptyl, carboxyl,
hydroxyl, straight-chain or branched acyl, alkoxy, alkylthio or
alkoxycarbonyl having in each case up to 6 carbon atoms, nitro,
cyano, halogen, phenyl or straight-chain or branched alkyl having
up to 6 carbon atoms which for its part may be substituted by
hydroxyl, amino, azido, carboxyl, straight-chain or branched acyl,
alkoxy, alkoxycarbonyl or acylamino having in each case up to 5
carbon atoms or by a radical of the formula --OR.sup.4 in which
R.sup.4 represents straight-chain or branched acyl having up to 5
carbon atoms and/or is substituted by a radical of the formula
144or --S(O).sub.c--NR.sup.6R.sup.7 in which a, b and b' are
identical or different and each represents a number 0, 1, 2 or 3,
R.sup.5 is hydrogen or straight-chain or branched alkyl having up
to 4 carbon atoms, c is a number 1 or 2 and R.sup.6 and R.sup.7 are
identical or different and each represents 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 may be
substituted by halogen, or represents aryl having 6 to 10 carbon
atoms which is optionally substituted by halogen, or represents
cycloalkyl having 3 to 7 carbon atoms, or R.sup.6 and R.sup.7
together with the nitrogen atom form a 5- to 7-membered saturated
heterocycle which may optionally contain a further oxygen atom or a
radical --NR.sup.8 in which R.sup.8 represents hydrogen,
straight-chain or branched alkyl having up to 4 carbon atoms or a
radical of the formula 145or benzyl or phenyl where the ring
systems are optionally substituted by halogen, and which is
substituted by at least one radical from the group (ii) consisting
of a 3- to 8-membered ring which may be saturated, unsaturated or
partially unsaturated, contains 1 to 4 heteroatoms from the group
consisting of N, O, and S, said S heteroatoms optionally bearing 1
or 2 oxygens, and which may also be attached via N, and which is
optionally mono- or polysubstituted by a 5- or 6-membered ring
which contains two oxygen atoms as ring members and forms a
bicyclic unit or a spiro unit with the 3- to 8-membered ring,
and/or by hydroxyl, cyano, straight-chain or branched alkyl, acyl
or alkoxycarbonyl having in each case up to 6 carbon atoms, where
alkyl, acyl and alkoxycarbonyl may be substituted by hydroxyl,
amino, halogen, carboxyl, straight-chain or branched acyl, alkoxy,
alkoxycarbonyl or acylamino having in each case up to 5 carbon
atoms, and an aryl ring having 6 to 10 carbon atoms which is
substituted by straight-chain or branched alkyl having up to 4
carbon atoms, and (C.sub.2-C.sub.10)alkenyl- ,
(C.sub.2-C.sub.10)alkinyl, (C.sub.7-C.sub.20)alkyl, which is
optionally substituted by aryl, heteroaryl, halogen, cyano,
dialkylamino, cycloalkyl, alkylamine, hydroxyl, amino, azido,
carboxyl, straight-chain or branched acyl, alkoxy, alkoxycarbonyl
or acylamino having in each case up to 5 carbon atoms or by a
radical of the formula --OR.sup.4 in which R.sup.4 represents
straight-chain or branched acyl having up to 5 carbon atoms and
(C.sub.1-C.sub.6)alkyl which is substituted 1- to 3 times by aryl,
heteroaryl, halogen(s), cyano, dialkylamino, alkylamino or
cycloalkyl and acyl, which is substituted by halogen(s), or by
acyloxy, arylthio or heteroarylthio, and --NO or radicals of the
formulae --SO.sub.3H and --S(O).sub.dR.sup.9, in which d represents
a number 1 or 2, R.sup.9 represents straight-chain or branched
alkyl having 1 to 10 carbon atoms, cycloalkyl having 3 to 8 carbon
atoms, aryl having 6 to 10 carbon atoms or an unsaturated 5- to
6-membered heterocycle having up to 3 heteroatoms from the group
consisting of S, N and O, where the ring systems may optionally be
substituted by halogen or by straight-chain or branched alkyl or
alkoxy having in each case up to 4 carbon atoms, and a radical of
the formula PO(OR.sup.10)(OR.sup.11) in which R.sup.10 and R.sup.11
are identical or different and each represents hydrogen,
straight-chain or branched alkyl having up to 8 carbon atoms or
cycloalkyl having 3 to 8 carbon atoms, aryl having 6 to 10 carbon
atoms or benzyl, and oxycycloalkyl having 3 to 8 ring members or
radicals of the formulae --CON.dbd.C(NH.sub.2).sub.2,
--C.dbd.NH(NH.sub.2), --NH--C(.dbd.NH)NH.sub.2 or
(CO).sub.eNR.sup.12R.sup.13 in which e represents a number 0 or 1,
R.sup.12 and R.sup.13 are identical or different and each
represents hydrogen, straight-chain or branched alkyl having up to
14 carbon atoms or cycloalkyl having 3 to 14 carbon atoms, aryl
having 6 to 10 carbon atoms or a saturated or unsaturated 3- to
10-membered ring having up to 5 heteroatoms from the group
consisting of N, O, S, where the abovementioned radicals may
optionally be substituted by aryl having 6 to 10 carbon atoms,
heterocyclyl, cycloalkyl having 3 to 7 carbon atoms, hydroxyl,
amino or straight-chain or branched alkoxy, acyl or alkoxycarbonyl
having in each case up to 6 carbon atoms, and, in the case that
e=1, R.sup.12 and R.sup.13, together with the nitrogen atom to
which they are attached, may also form a 5- or 6-membered ring
having up to 3 heteroatoms from the group consisting of N, O, S,
which may optionally be substituted up to 3 times by hydroxyl,
alkoxy or alkyl having in each case up to 8 carbon atoms, and, in
the case that e=0, R.sup.12 and R.sup.13 may also represent
straight-chain, branched or cyclic acyl having up to 14 carbon
atoms, hydroxyalkyl, straight-chain or branched alkoxycarbonyl or
acyloxyalkyl having in each case up to 6 carbon atoms, or a radical
of the formula --SO.sub.2R.sup.14 in which R.sup.14 represents
straight-chain or branched alkyl having up to 4 carbon atoms,
and/or R.sup.12 and R.sup.13 also represent radicals of the
formulae 146in which R.sup.15-R.sup.16 and R.sup.18-R.sup.31 are
identical or different and each represents hydrogen or
straight-chain or branched alkyl having up to 4 carbon atoms, g
represents a number 0, 1 or 2, and R.sup.17 represents phenyl,
straight-chain or branched alkyl having up to 6 carbon atoms or
cycloalkyl having 3 to 8 carbon atoms, with the proviso that, if
e=0, R.sup.12 and R.sup.13 do not simultaneously represent
hydrogen, or R.sup.1 represents a purine radical which may
optionally be substituted up to three times by halogen, azido,
cyano, hydroxyl, amino, monoalkylamino having up to 5 carbon atoms,
dialkylamino having in each case up to 5 carbon atoms, alkyl having
up to 5 carbon atoms and/or alkoxy having up to 5 carbon atoms,
R.sup.2 and R.sup.3, together with the double bond, form a
6-membered saturated or aromatic heterocycle having up to 3
heteroatoms from the group consisting of N, S and O, which is
optionally substituted up to three times by identical or different
substituents from the group consisting of formyl, carboxyl,
hydroxyl, mercaptyl, straight-chain or branched acyl, alkylthio or
alkoxycarbonyl having in each case up to 6 carbon atoms, nitro,
cyano, halogen or straight-chain or branched alkyl or alkoxy having
in each case up to 6 carbon atoms which for its part may be
substituted by hydroxyl, amino, carboxyl, straight-chain or
branched acyl, alkoxy or alkoxycarbonyl having in each case up to 5
carbon atoms, and/or which is optionally substituted by a group of
the formula --NR.sup.32R.sup.33 in which R.sup.32 and R.sup.33 are
identical or different and each represents hydrogen or
straight-chain or branched alkyl having up to 6 carbon atoms, or
R.sup.32 represents hydrogen and R.sup.33 represents acyl, and/or
which is optionally substituted by phenyl which for its part may be
substituted up to 2 times by identical or different substituents
from the group consisting of halogen and straight-chain or branched
alkyl or alkoxy having in each case up to 6 carbon atoms, and/or
which is optionally substituted by a group of the formula
--N.dbd.CH--NR.sup.34R.s- up.35 in which R.sup.34 and R.sup.35 are
identical or different and each represents hydrogen, phenyl or
straight-chain or branched alkyl having up to 6 carbon atoms, A
represents a 5- or 6-membered aromatic or saturated heterocycle
having up to 3 heteroatoms from the group consisting of S, N and O
or represents phenyl, which are optionally substituted up to 3
times by identical or different substituents from the group
consisting of amino, mercaptyl, hydroxyl, formyl, carboxyl,
straight-chain or branched acyl, alkylthio, alkyloxyacyl, alkoxy or
alkoxycarbonyl having in each case 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 may
be substituted by hydroxyl, carboxyl, straight-chain or branched
acyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon
atoms, and/or is substituted by a group of the formula
--(CO).sub.h--NR.sup.36R.sup.37 in which h represents a number 0 or
1, R.sup.36 and R.sup.37 are identical or different and each
represents hydrogen, phenyl, benzyl or straight-chain or branched
alkyl or acyl having in each case up to 5 carbon atoms, or a
stereoisomeric form or salt thereof.
2. The compound of formula (I) according to claim 1 in which
R.sup.1 represents a saturated or aromatic 6-membered heterocycle
having up to 3 heteroatoms from the group consisting of S, N and O,
which may be attached via a nitrogen atom, and which is optionally
substituted up to 2 times by identical or different radicals from
the group (i) consisting of hydrogen, amino, azido, formyl,
mercaptyl, carboxyl, hydroxyl, straight-chain or branched acyl,
alkoxy, alkylthio or alkoxycarbonyl having in each case up to 6
carbon atoms, nitro, cyano, halogen, phenyl or straight-chain or
branched alkyl having up to 6 carbon atoms which for its part may
be substituted by hydroxyl, amino, azido, carboxyl, straight-chain
or branched acyl, alkoxy, alkoxycarbonyl or acylamino having in
each case up to 5 carbon atoms or by a radical of the formula
--OR.sup.4 in which R.sup.4 represents straight-chain or branched
acyl having up to 5 carbon atoms and/or is substituted by a radical
of the formula 147in which a, b and b' are identical or different
and each represents a number 0, 1, 2 or 3, R.sup.5 is hydrogen or
straight-chain or branched alkyl having up to 4 carbon atoms, and
which is substituted by at least one radical from the group (ii)
consisting of a 3- to 8-membered ring which may be saturated,
unsaturated or partially unsaturated, contains 1 to 4 heteroatoms
from the group consisting of N, O, and S, said S heteroatoms
optionally bearing 1 or 2 oxygens and which may also be attached
via N, and which is optionally mono- or polysubstituted by a 5- or
6-membered ring which contains two oxygen atoms as ring members and
forms a bicyclic unit or a spiro unit with the 3- to 8-membered
ring, and/or by hydroxyl, cyano, straight-chain or branched alkyl,
acyl or alkoxycarbonyl having in each case up to 6 carbon atoms,
where alkyl, acyl and alkoxycarbonyl may be substituted by
hydroxyl, amino, halogen, carboxyl, straight-chain or branched
acyl, alkoxy, alkoxycarbonyl or acylamino having in each case up to
5 carbon atoms, and an aryl ring having 6 to 10 carbon atoms which
is substituted by straight-chain or branched alkyl having up to 4
carbon atoms, and (C.sub.2-C.sub.10)alkenyl,
(C.sub.2-C.sub.10)alkinyl, (C.sub.7-C.sub.20)alkyl, which is
optionally substituted by aryl, heteroaryl, halogen, cyano,
dialkylamino, cycloalkyl, alkylamine, hydroxyl, amino, azido,
carboxyl, straight-chain or branched acyl, alkoxy, alkoxycarbonyl
or acylamino having in each case up to 5 carbon atoms or by a
radical of the formula --OR.sup.4 in which R.sup.4 represents
straight-chain or branched acyl having up to 5 carbon atoms and
(C.sub.1-C.sub.6)alkyl which is substituted 1- to 3 times by aryl,
heteroaryl, halogen(s), cyano, dialkylamino, alkylamino or
cycloalkyl and acyl, which is substituted by halogen(s), or by
acyloxy, arylthio or heteroarylthio, and --NO or radicals of the
formulae --SO.sub.3H and --S(O).sub.dR.sup.9, in which d represents
a number 1 or 2, R.sup.9 represents straight-chain or branched
alkyl having 1 to 10 carbon atoms, cycloalkyl having 3 to 8 carbon
atoms, aryl having 6 to 10 carbon atoms or an unsaturated 5- to
6-membered heterocycle having up to 3 heteroatoms from the group
consisting of S, N and O, where the ring systems may optionally be
substituted by halogen or by straight-chain or branched alkyl or
alkoxy having in each case up to 4 carbon atoms, and a radical of
the formula PO(OR.sup.10)(OR.sup.11) in which R.sup.10 and R.sup.11
are identical or different and each represents hydrogen,
straight-chain or branched alkyl having up to 8 carbon atoms or
cycloalkyl having 3 to 8 carbon atoms, aryl having 6 to 10 carbon
atoms or benzyl, and oxycycloalkyl having 3 to 8 ring members or
radicals of the formulae --CON.dbd.C(NH.sub.2).sub.2,
--C.dbd.NH(NH.sub.2), --NH--C(.dbd.NH)NH.sub.2 or
(CO).sub.eNR.sup.12R.sup.13 in which e represents a number 0 or 1,
R.sup.12 and R.sup.13 are identical or different and each
represents hydrogen, straight-chain or branched alkyl having up to
14 carbon atoms or cycloalkyl having 3 to 14 carbon atoms, aryl
having 6 to 10 carbon atoms or a saturated or unsaturated 3- to
10-membered ring having up to 5 heteroatoms from the group
consisting of N, O, S, where the abovementioned radicals may
optionally be substituted by aryl having 6 to 10 carbon atoms,
heterocyclyl, cycloalkyl having 3 to 7 carbon atoms, hydroxyl,
amino or straight-chain or branched alkoxy, acyl or alkoxycarbonyl
having in each case up to 6 carbon atoms, and, in the case that
e=1, R.sup.12 and R.sup.13, together with the nitrogen atom to
which they are attached, may also form a 5- or 6-membered ring
having up to 3 heteroatoms from the group consisting of N, O, S,
which may optionally substituted up to 3 times by hydroxyl, alkoxy
or alkyl having in each case up to 8 carbon atoms, and, in the case
that e=0, R.sup.12 and R.sup.13 may also represent straight-chain,
branched or cyclic acyl having up to 14 carbon atoms, hydroxyalkyl,
straight-chain or branched alkoxycarbonyl or acyloxyalkyl having in
each case up to 6 carbon atoms, or a radical of the formula
--SO.sub.2R.sup.14 in which R.sup.14 represents straight-chain or
branched alkyl having up to 4 carbon atoms, and/or R.sup.12 and
R.sup.13 also represent radicals of the formulae 148in which
R.sup.15-R.sup.16 and R.sup.18-R.sup.31 are identical or different
and each represents hydrogen or straight-chain or branched alkyl
having up to 4 carbon atoms, g represents a number 0, 1 or 2, and
R.sup.17 represents phenyl, straight-chain or branched alkyl having
up to 6 carbon atoms or cycloalkyl having 3 to 8 carbon atoms, with
the proviso that, if e=0, R.sup.12 and R.sup.13 do not
simultaneously represent hydrogen, or R.sup.1 represents a purine
radical which may optionally be substituted up to three times by
halogen, azido, cyano, hydroxyl, amino, monoalkylamino having up to
5 carbon atoms, dialkylamino having in each case up to 5 carbon
atoms, alkyl having up to 5 carbon atoms and/or alkoxy having up to
5 carbon atoms, R.sup.2 and R.sup.3, together with the double bond,
form a fused pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl ring,
which are optionally substituted up to 2 times by identical or
different substituents from the group consisting of formyl,
carboxyl, hydroxyl, mercaptyl, straight-chain or branched acyl,
alkylthio or alkoxycarbonyl having in each case up to 5 carbon
atoms, nitro, cyano, azido, fluorine, chlorine, bromine or
straight-chain or branched alkyl or alkoxy having in each case up
to 5 carbon atoms which for its part may be substituted by
hydroxyl, amino, carboxyl, straight-chain or branched acyl, alkoxy
or alkoxycarbonyl having in each case up to 4 carbon atoms, and/or
the abovementioned heterocyclic rings are optionally substituted by
a group of the formula --NR.sup.32R.sup.33 in which R.sup.32 and
R.sup.33 are identical or different and represent hydrogen or
straight-chain or branched alkyl having up to 4 carbon atoms or
R.sup.32 represents hydrogen and R.sup.33 represents formyl and/or
the abovementioned fused pyridyl, pyrimidinyl, pyrazinyl or
pyridazinyl rings are optionally substituted by phenyl which for
its part may be substituted by fluorine, chlorine, bromine or by
straight-chain or branched alkyl or alkoxy having in each case up
to 4 carbon atoms, A represents thienyl, tetrahydropyranyl,
tetrahydrofuranyl, phenyl, morpholinyl, pyrimidyl, pyrazinyl,
pyridazinyl or pyridyl which are optionally substituted up to 2
times by identical or different substituents from the group
consisting of hydroxyl, formyl, carboxyl, straight-chain or
branched acyl, alkylthio, alkyloxyacyl, alkoxy or alkoxycarbonyl
having in each case up to 4 carbon atoms, fluorine, chlorine and
bromine, or a stereoisomeric form or salt thereof.
3. The compound of formula (I) according to claim 1 in which
R.sup.1 represents a pyrimidine radical which is optionally
substituted up to 2 times by identical or different radicals from
the group (i) consisting of hydrogen, amino, hydroxyl, alkoxy or
alkoxycarbonyl having in each case up to 3 carbon atoms, cyano or
halogen, and which is substituted by at least one radical from the
group (ii) consisting of a 5- to 6-membered ring which may be
saturated, unsaturated or partially unsaturated, which contains 1
to 3 heteroatoms from the group consisting of N, O, and S, said S
heteroatoms optionally bearing 1 or 2 oxygens, and which may also
be attached via N, and which is optionally mono- or polysubstituted
by a 5-membered ring which contains two oxygen atoms as ring
members and which forms, with the 3- to 8-membered ring, a bicyclic
unit or a spiro unit, such as, for example, a
1,4-dioxa-8-azaspiro[4.5]decane or
1.5-dioxa-9-azaspiro[5.5]undecane radical, and/or by hydroxyl,
cyano, straight-chain or branched alkyl, acyl or alkoxycarbonyl
having in each case up to 3 carbon atoms, where alkyl, acyl and
alkoxycarbonyl may be substituted by hydroxyl, amino, halogen,
carboxyl, straight-chain or branched acyl or alkoxy having in each
case up to 3 carbon atoms, and a tolyl radical, and C.sub.7-alkyl
which is optionally substituted by cyano, and
(C.sub.1-C.sub.5)alkyl, which is 1- to 3-times substituted by
halogen(s), cyano, aryl and acyloxy, and --NO or radicals of the
formula --S(O).sub.dR.sup.9, in which d represents a number 1 or 2,
R.sup.9 represents straight-chain or branched alkyl having 1 to 4
carbon atoms, aryl having 6 carbon atoms or thienyl, and a radical
of the formula PO(OR.sup.10)(OR.sup.11), in which R.sup.10 and
R.sup.11 are identical or different and each represents
straight-chain or branched alkyl having up to 3 carbon atoms, and
radicals of the formulae --NH--C(.dbd.NH)NH.sub.2 and
(CO).sub.eNR.sup.12R.sup.13 in which e represents a number 0 or 1,
R.sup.12 and R.sup.13 are identical or different and each
represents hydrogen, straight-chain or branched alkyl having up to
4 carbon atoms or cycloalkyl having 3 carbon atoms, where the
abovementioned radicals may optionally be substituted by aryl
having 6 carbon atoms, furyl, cycloalkyl having 3 carbon atoms,
hydroxyl, straight-chain alkoxy having up to 2 carbon atoms, and,
in the case that e=1, R.sup.12 and R.sup.13, together with the
nitrogen atom to which they are attached, may also form a 5- or
6-membered ring having up to 2 heteroatoms from the group
consisting of N, O, S which may optionally be substituted up to 2
times by hydroxyl or methyl, and, in the case that e=0, R.sup.12
and R.sup.13 may also represent straight-chain acyl having up to 14
carbon atoms, and/or R.sup.12 and R.sup.13 also represent a radical
of the formula 149with the proviso that in the case that e=0,
R.sup.12 and R.sup.13 do not simultaneously represent hydrogen, or
R.sup.1 represents a purine radical which may optionally be
substituted up to two times by halogen, azido, amino,
monoalkylamino having up to 4 carbon atoms and/or methyl, R.sup.2
and R.sup.3 together with the double bond form a pyridyl or
pyrimidinyl ring, A represents phenyl or pyrimidyl, which are
optionally substituted by fluorine, chlorine or bromine, or a
stereoisomeric form or salt thereof.
4. The compound according to claim 1 where R.sup.1 represents a
radical of the formula 150in which R' represents NH.sub.2, R"
represents optionally substituted morpholinyl, piperidinyl,
piperazinyl, pyrrolidinyl, triazolyl or thiomorpholinyl and R'"
represents hydrogen or NH.sub.2.
5. The compound according to claim 4 in which R" represents
morpholinyl.
6. A process for preparing the compounds of the formula (I)
according to claim 1, characterized in that depending on the
various meanings of the heterocycles listed above under R.sup.2 and
R.sup.3 [A] a compound of the formulaR.sup.1--D (II)in which
R.sup.1 is as defined above in claim 1 and D represents a radical
selected from the formulae 151in which R.sup.38 represents
C.sub.1-C.sub.4-alkyl is converted, by reaction with a compound of
the formula (III)A--CH.sub.2--NH--NH.sub.2 (III)in which A is as
defined above in claim 1 in inert solvent, if appropriate in the
presence of a base, into a compound of the formula (IV) or (IVa)
152in which A and R.sup.1 are each as defined above in claim 1,
and, in the case of the compound of the formula (IVa), is
subsequently cyclized with a carboxylic acid, nitrile, formamide or
guanidium salt, and, in the case of the compound of the formula
(IV), is cyclized with a 1,3-dicarbonyl derivative, its salt,
tautomer, enol ether or enamine, in the presence of acid, or [B] in
the case that R.sup.2 and R.sup.3 together form a pyrazine ring, a
compound of the formula (IV) is initially converted by nitrosation
into a compound of the formula (V) 153in which A and R.sup.1 are
each as defined above, in claim 1 in a second step, compound of the
formula (VI) 154in which A and R.sup.1 are each as defined above in
claim 1 is prepared by a reduction, and these are this is
subsequently cyclized with a 1,2-dicarbonyl compound, or [C] a
compound of the formula (VII) 155in which A.sup.1, R.sup.2 and
R.sup.3 are each as defined above in claim 1 and L represents a
radical of the formula --SnR.sup.39R.sup.40R.sup.41, ZnR.sup.42,
iodine, bromine or triflate in which R.sup.39, R.sup.40 and
R.sup.41 are identical or different and each represents
straight-chain or branched alkyl having up to 4 carbon atoms and
R.sup.42 represents halogen is reacted with a compound of the
formula (VIII)R.sup.1--T (VIII),in which R.sup.1 is as defined
above in claim 1 and in the case that L=SnR.sup.39R.sup.40R.sup.41
or ZnR.sup.42, T represents triflate or represents halogen, and, in
the case that L=iodine, bromine or triflate, T represents a radical
of the formula SnR.sup.39'R.sup.40'R.sup.41', ZnR.sup.42' or
BR.sup.43'R.sup.44' in which R.sup.39', R.sup.40', R.sup.41' and
R.sup.42' have the meanings of R.sup.39, R.sup.40, R.sup.41 and
R.sup.42 given above and are identical to or different from them,
R.sup.43' and R.sup.44' are identical or different and each
represents hydroxyl, aryloxy having 6 to 10 carbon atoms or
straight-chain or branched alkyl or alkoxy having in each case up
to 5 carbon atoms, or together form a 5- or 6-membered carbocyclic
ring in a palladium-catalysed reaction in inert solvent, or [D] in
the case that R.sup.1 represents an optionally substituted
pyrimidine radical, an amidine of the formula (IX) 156in which A,
R.sup.2 and R.sup.3 are each as defined above in claim 1 is reacted
with a compound of the formula (X), (Xa), (Xb) or (Xc) 157in which
R.sup.1' represents the optionally substituted cycloalkyl radical
listed above under R.sup.1; Alk represents straight-chain or
branched alkyl having up to 8 carbon atoms, and Z represents an
NH.sub.2 group, a monoalkylamino group having up to 7 carbon atoms,
a dialkylamino group having up to 7 carbon atoms, a piperidinyl or
morpholinyl radical which is attached via the nitrogen, hydroxyl,
alkoxy having up to 7 carbon atoms, acyloxy having up to 7 carbon
atoms or aroyloxy having 6 to 10 carbon atoms, and, in the case of
the groups --S(O).sub.cNR.sup.6R.sup.7 and
--S(O).sub.c'NR.sup.6'R.sup.7'- , starting from the unsubstituted
compound of the formula (I), reacted initially with thionyl
chloride and, in a second step, with an appropriate amine and, if
appropriate, the substituents listed under X, Y, R.sup.1, R.sup.2,
R.sup.3 and/or R.sup.4 are modified or introduced by acylation of
free amino groups or hydroxyl groups, chlorination, catalytic
hydrogenation, reduction, oxidation, removal of protective groups
and/or nucleophilic substitution.
7. A pharmaceutical composition comprising a compound of the
formula (I) according to claim 1 and a pharmaceutically acceptable
carrier.
8. Cancelled
9. A pharmaceutical composition comprising at least one compound of
the general formula (I) according to claim 1 in combination with an
organic nitrate or NO donor.
10. A pharmaceutical composition comprising at least one compound
of the formula (I) according to claim 1 in combination with a
compound which inhibits the degradation of cyclic guanosine
monophosphate (cGMP).
11. Cancelled
12. A method for treating a cardiovascular disease comprising
administering to a mammal an effective amount of a compound
according to claim 1.
13. The method of claim 12, wherein said cardiovascular disease is
hypertension.
14. A method of treating thromboembolic disorders and ischemia
comprising administering to a mammal an effective amount of a
compound according to claim 1.
15. A method of treating sexual dysfunction comprising
administering to a mammal an effective amount of a compound
according to claim 1.
16. A method of treating inflammation comprising administering to a
mammal an effective amount of a compound according to claim 1.
17. The method of claim 12, 13, 14, 15, or 16 wherein the a
compound of the general formula (I) according to claim 1 is
administered in combination with an organic nitrate or NO
donor.
18. The compound of claim 1, wherein when said radical from group
(ii) is a 3- to 8-membered ring, this ring is selected from the
group consisting of imidazolyl, imidazolinyl, imidazolidinyl,
morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, triazolyl,
pyrrolyl, thiomorpholinyl, S-oxothiomorpholinyl and
S,S-dioxothiomorpholinyl.
19. The compound of claim 2, wherein when said radical from group
(ii) is a 3- to 8-membered ring, this ring is selected from the
group consisting of imidazolyl, imidazolinyl, imidazolidinyl,
morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, triazolyl,
pyrrolyl, thiomorpholinyl, S-oxothiomorpholinyl and
S,S-dioxothiomorpholinyl.
20. The compound of claim 3, wherein when said radical from group
(ii) is a 5- to 6-membered ring, this ring is selected from the
group consisting of imidazolyl, imidazolinyl, imidazolidinyl,
morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, triazolyl,
pyrrolyl and thiomorpholinyl.
21. The process of claim 6, wherein when said compound of the
general formula (IV) is cyclized with a 1,3-dicarbonyl derivative,
its salt, tautomer, enol ether or enamine in the presence of acid,
this is carried out under microwave radiation.
22 The process of claim 6 wherein in part [B] the 1,2-dicarbonyl
compound used in said cyclization with the compound of formula (VI)
is aqueous glyoxal solution.
23. The method of claim 12, 13, 14, 15 or 16 wherein the compounds
of general formula (I) according to claim 1 are administered in
combination with a compound which inhibits the degradation of
cyclic guanosine monophosphate (cGMP).
Description
[0001] The present invention relates to novel substituted pyrazole
derivatives, to processes for their preparation and to their use as
medicaments, in particular as medicaments for the treatment of
cardiovascular disorders according to claims 1 to 10.
[0002] It is already known that 1-benzyl-3-(substituted
heteroaryl)-fused pyrazole derivatives inhibit thromocyte
aggregation (cf. EP 667 345 A1).
[0003] WO 98/16223 discloses the use of 1-benzyl-3-(substituted
hetaryl)-fused pyrazole derivatives for the treatment of specific
disorders of the cardiovascular system and the central nervous
system.
[0004] WO 98/16507 discloses heterocyclylmethyl-substituted
pyrazole derivatives and their use in the treatment of
cardiovascular disorders.
[0005] WO 98/23619 likewise discloses substituted pyrazole
derivatives for the treatment of cardiovascular disorders.
[0006] The present invention relates to substituted pyrazole
derivatives of the general formula (I) 2
[0007] in which
[0008] R.sup.1 represents a saturated or aromatic 5- or 6-membered
heterocycle having up to 3 heteroatoms from the group consisting of
S, N and O, which may be attached via a nitrogen atom,
[0009] and which is optionally substituted up to 2 times by
identical or different radicals from the group (i) consisting
of
[0010] hydrogen, amino, azido, formyl, mercaptyl, carboxyl,
hydroxyl, straight-chain or branched acyl, alkoxy, alkylthio or
alkoxy-carbonyl having in each case up to 6 carbon atoms, nitro,
cyano, halogen, phenyl or straight-chain or branched alkyl having
up to 6 carbon atoms which for its part may be substituted by
hydroxyl, amino, azido, carboxyl, straight-chain or branched acyl,
alkoxy, alkoxycarbonyl or acylamino having in each case up to 5
carbon atoms or by a radical of the formula --OR.sup.4
[0011] in which
[0012] R.sup.4 represents straight-chain or branched acyl having up
to 5 carbon atoms
[0013] and/or is substituted by a radical of the formula 3
[0014] or
[0015] --S(O).sub.c--NR.sup.6R.sup.7
[0016] in which
[0017] a, b and b' are identical or different and each represents a
number 0, 1, 2 or 3,
[0018] R.sup.5 is hydrogen or straight-chain or branched alkyl
having up to 4 carbon atoms,
[0019] c is a number 1 or 2 and
[0020] R.sup.6 and R.sup.7 are identical or different and each
represents 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 may be substituted by halogen,
[0021] or
[0022] represents aryl having 6 to 10 carbon atoms which is
optionally substituted by halogen,
[0023] or
[0024] represents cycloalkyl having 3 to 7 carbon atoms,
[0025] or
[0026] R.sup.6 and R.sup.7 together with the nitrogen atom form a
5- to 7-membered saturated heterocycle which may optionally contain
a further oxygen atom or a radical --NR.sup.8
[0027] in which
[0028] R.sup.8 represents hydrogen, straight-chain or branched
alkyl having up to 4 carbon atoms or a radical of the formula 4
[0029] or benzyl or phenyl where the ring systems are optionally
substituted by halogen,
[0030] and which is substituted by at least one radical from the
group (ii) consisting of
[0031] a 3- to 8-membered ring which may be saturated, unsaturated
or partially unsaturated, contains 1 to 4 heteroatoms from the
group consisting of N, O, S, SO, SO.sub.2 and which may also be
attached via N, imidazolyl, imidazolinyl, imidazolidinyl,
morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, triazolyl,
pyrrolyl, thiomorpholinyl, S-oxothiomorpholinyl and
S,S-dioxothiomorpholinyl being particularly preferred, and which is
optionally mono- or polysubstituted by a 5- or 6-membered ring
which contains two oxygen atoms as ring members and forms a
bicyclic unit or a spiro unit with the 3- to 8-membered ring,
and/or by hydroxyl, cyano, straight-chain or branched alkyl, acyl
or alkoxycarbonyl having in each case up to 6 carbon atoms, where
alkyl, acyl and alkoxycarbonyl may be substituted by hydroxyl,
amino, halogen, carboxyl, straight-chain or branched acyl, alkoxy,
alkoxycarbonyl or acylamino having in each case up to 5 carbon
atoms,
[0032] and
[0033] an aryl ring having 6 to 10 carbon atoms which is
substituted by straight-chain or branched alkyl having up to 4
carbon atoms,
[0034] and
[0035] (C.sub.2-C.sub.10)alkenyl, (C.sub.2-C.sub.10)alkinyl,
(C.sub.7-C.sub.20)alkyl, which is optionally substituted by aryl,
heteroaryl, halogen, cyano, dialkylamino, cycloalkyl, alkylamine,
hydroxyl, amino, azido, carboxyl, straight-chain or branched acyl,
alkoxy, alkoxycarbonyl or acylamino having in each case up to 5
carbon atoms or by a radical of the formula --OR.sup.4
[0036] in which
[0037] R.sup.4 represents straight-chain or branched acyl having up
to 5 carbon atoms
[0038] and
[0039] (C.sub.1-C.sub.6)alkyl which is substituted 1- to 3 times by
aryl, heteroaryl, halogen(s), cyano, dialkylamino, alkylamino or
cycloalkyl
[0040] and
[0041] acyl, which is substituted by halogen(s), particularly
preferably by fluorine, or by acyloxy, arylthio or
heteroarylthio,
[0042] and
[0043] --NO or radicals of the formulae --SO.sub.3H and
--S(O).sub.dR.sup.9,
[0044] in which
[0045] d represents a number 1 or 2,
[0046] R.sup.9 represents straight-chain or branched alkyl having 1
to 10 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, aryl
having 6 to 10 carbon atoms or a saturated or unsaturated 5- to
6-membered heterocycle having up to 3 heteroatoms from the group
consisting of S, N and O, where the ring systems may optionally be
substituted by halogen or by straight-chain or branched alkyl or
alkoxy having in each case up to 4 carbon atoms,
[0047] and
[0048] a radical of the formula PO(OR.sup.10)(OR.sup.11)
[0049] in which
[0050] R.sup.10 and R.sup.11 are identical or different and each
represents hydrogen, straight-chain or branched alkyl having up to
8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms, aryl
having 6 to 10 carbon atoms or benzyl,
[0051] and
[0052] oxycycloalkyl having 3 to 8 ring members or radicals of the
formulae --CON.dbd.C(NH.sub.2).sub.2, --C.dbd.NH(NH.sub.2),
--NH--C(.dbd.NH)NH.sub.2 or (CO).sub.eNR.sup.12R.sup.13
[0053] in which
[0054] e represents a number 0 or 1,
[0055] R.sup.12 and R.sup.13 are identical or different and each
represents hydrogen, straight-chain or branched alkyl having up to
14 carbon atoms or cycloalkyl having 3 to 14 carbon atoms, aryl
having 6 to 10 carbon atoms or a saturated or unsaturated 3- to
10-membered ring having up to 5 heteroatoms from the group
consisting of N, O, S, where the abovementioned radicals may
optionally be substituted by aryl having 6 to 10 carbon atoms,
heterocyclyl, cycloalkyl having 3 to 7 carbon atoms, hydroxyl,
amino or straight-chain or branched alkoxy, acyl or alkoxycarbonyl
having in each case up to 6 carbon atoms,
[0056] and, in the case that e=1,
[0057] R.sup.12 and R.sup.13, together with the nitrogen atom to
which they are attached, may also form a 5- or 6-membered ring
having up to 3 heteroatoms from the group consisting of N, O, S,
which may optionally be substituted up to 3 times by hydroxyl,
alkoxy or alkyl having in each case up to 8 carbon atoms,
[0058] and, in the case that e=0,
[0059] R.sup.12 and R.sup.13 may also represent straight-chain,
branched or cyclic acyl having up to 14 carbon atoms, hydroxyalkyl,
straight-chain or branched alkoxycarbonyl or acyloxyalkyl having in
each case up to 6 carbon atoms, or a radical of the formula
--SO.sub.2R.sup.14
[0060] in which
[0061] R.sup.14 represents straight-chain or branched alkyl having
up to 4 carbon atoms,
[0062] and/or
[0063] R.sup.12 and R.sup.13 also represent radicals of the
formulae 5
[0064] in which
[0065] R.sup.15-R.sup.16 and R.sup.18-R.sup.31 are identical or
different and each represents hydrogen or straight-chain or
branched alkyl having up to 4 carbon atoms,
[0066] g represents a number 0, 1 or 2,
[0067] and
[0068] R.sup.17 represents phenyl, straight-chain or branched alkyl
having up to 6 carbon atoms or cycloalkyl having 3 to 8 carbon
atoms,
[0069] with the proviso that, if e=0, R.sup.12 and R.sup.13 do not
simultaneously represent hydrogen,
[0070] or
[0071] R.sup.1 represents a purine radical which may optionally be
substituted up to three times by halogen, azido, cyano, hydroxyl,
amino, monoalkylamino having up to 5 carbon atoms, dialkylamino
having in each case up to 5 carbon atoms, alkyl having up to 5
carbon atoms and/or alkoxy having up to 5 carbon atoms,
[0072] R.sup.2 and R.sup.3, together with the double bond, form a
6-membered saturated or aromatic heterocycle having up to 3
heteroatoms from the group consisting of N, S and O,
[0073] which is optionally substituted up to three times by
identical or different substituents from the group consisting of
formyl, carboxyl, hydroxyl, mercaptyl, straight-chain or branched
acyl, alkylthio or alkoxycarbonyl having in each case up to 6
carbon atoms, nitro, cyano, halogen or straight-chain or branched
alkyl or alkoxy having in each case up to 6 carbon atoms which for
its part may be substituted by hydroxyl, amino, carboxyl,
straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in
each case up to 5 carbon atoms,
[0074] and/or which is optionally substituted by a group of the
formula --NR.sup.32R.sup.33
[0075] in which
[0076] R.sup.32 and R.sup.33 are identical or different and each
represents hydrogen or straight-chain or branched alkyl having up
to 6 carbon atoms,
[0077] or
[0078] R.sup.32 represents hydrogen and
[0079] R.sup.33 represents acyl,
[0080] and/or which is optionally substituted by phenyl which for
its part may be substituted up to 2 times by identical or different
substituents from the group consisting of halogen and
straight-chain or branched alkyl or alkoxy having in each case up
to 6 carbon atoms,
[0081] and/or which is optionally substituted by a group of the
formula --N.dbd.CH--NR.sup.34R.sup.35
[0082] in which
[0083] R.sup.34 and R.sup.35 are identical or different and each
represents hydrogen, phenyl or straight-chain or branched alkyl
having up to 6 carbon atoms,
[0084] A represents a 5- or 6-membered aromatic or saturated
heterocycle having up to 3 heteroatoms from the group consisting of
S, N and O or represents phenyl, which are optionally substituted
up to 3 times by identical or different substituents from the group
consisting of amino, mercaptyl, hydroxyl, formyl, carboxyl,
straight-chain or branched acyl, alkylthio, alkyloxyacyl, alkoxy or
alkoxycarbonyl having in each case 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 may
be substituted by hydroxyl, carboxyl, straight-chain or branched
acyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon
atoms,
[0085] and/or is substituted by a group of the formula
--(CO).sub.h--NR.sup.36R.sup.37
[0086] in which
[0087] h represents a number 0 or 1,
[0088] R.sup.36 and R.sup.37 are identical or different and each
represents hydrogen, phenyl, benzyl or straight-chain or branched
alkyl or acyl having in each case up to 5 carbon atoms,
[0089] and their isomeric forms and salts.
[0090] Preference according to the invention is given to compounds
of the general formula (I)
[0091] in which
[0092] R.sup.1 represents a saturated or aromatic 6-membered
heterocycle having up to 3 heteroatoms from the group consisting of
S, N and O, which may be attached via a nitrogen atom,
[0093] and which is optionally substituted up to 2 times by
identical or different radicals from the group (i) consisting
of
[0094] hydrogen, amino, azido, formyl, mercaptyl, carboxyl,
hydroxyl, straight-chain or branched acyl, alkoxy, alkylthio or
alkoxy-carbonyl having in each case up to 6 carbon atoms, nitro,
cyano, halogen, phenyl or straight-chain or branched alkyl having
up to 6 carbon atoms which for its part may be substituted by
hydroxyl, amino, azido, carboxyl, straight-chain or branched acyl,
alkoxy, alkoxycarbonyl or acylamino having in each case up to 5
carbon atoms or by a radical of the formula --OR.sup.4
[0095] in which
[0096] R.sup.4 represents straight-chain or branched acyl having up
to 5 carbon atoms
[0097] and/or is substituted by a radical of the formula 6
[0098] or
[0099] in which
[0100] a, b and b' are identical or different and each represents a
number 0, 1, 2 or 3,
[0101] R.sup.5 is hydrogen or straight-chain or branched alkyl
having up to 4 carbon atoms,
[0102] and which is substituted by at least one radical from the
group (ii) consisting of
[0103] a 3- to 8-membered ring which may be saturated, unsaturated
or partially unsaturated, contains 1 to 4 heteroatoms from the
group consisting of N, O, S, SO, SO.sub.2 and which may also be
attached via N, imidazolyl, imidazolinyl, imidazolidinyl,
morpholinyl, piperidinyl, piperazinyl, pyrrolidine, triazolyl,
pyrrolyl, thiomorpholinyl, S-oxothiomorpholinyl and
S,S-dioxothiomorpholinyl being particularly preferred, and which is
optionally mono- or polysubstituted by a 5- or 6-membered ring
which contains two oxygen atoms as ring members and forms a
bicyclic unit or a spiro unit with the 3- to 8-membered ring,
and/or by hydroxyl, cyano, straight-chain or branched alkyl, acyl
or alkoxycarbonyl having in each case up to 6 carbon atoms, where
alkyl, acyl and alkoxycarbonyl may be substituted by hydroxyl,
amino, halogen, carboxyl, straight-chain or branched acyl, alkoxy,
alkoxycarbonyl or acylamino having in each case up to 5 carbon
atoms,
[0104] and
[0105] an aryl ring having 6 to 10 carbon atoms which is
substituted by straight-chain or branched alkyl having up to 4
carbon atoms,
[0106] and
[0107] (C.sub.2-C.sub.10)alkenyl, (C.sub.2-C.sub.10)alkinyl,
(C.sub.7-C.sub.20)alkyl, which is optionally substituted by aryl,
heteroaryl, halogen, cyano, dialkylamino, cycloalkyl, alkylamine,
hydroxyl, amino, azido, carboxyl, straight-chain or branched acyl,
alkoxy, alkoxycarbonyl or acylamino having in each case up to 5
carbon atoms or by a radical of the formula --OR.sup.4
[0108] in which
[0109] R.sup.4 represents straight-chain or branched acyl having up
to 5 carbon atoms
[0110] and
[0111] (C.sub.1-C.sub.6)alkyl which is substituted 1- to 3 times by
aryl, heteroaryl, halogen(s), cyano, dialkylamino, alkylamino or
cycloalkyl
[0112] and
[0113] acyl, which is substituted by halogen(s), particularly
preferably by fluorine, or by acyloxy, arylthio or
heteroarylthio,
[0114] and
[0115] --NO or radicals of the formulae --SO.sub.3H and
--S(O).sub.dR.sup.9,
[0116] in which
[0117] d represents a number 1 or 2,
[0118] R.sup.9 represents straight-chain or branched alkyl having 1
to 10 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, aryl
having 6 to 10 carbon atoms or a saturated or unsaturated 5- to
6-membered heterocycle having up to 3 heteroatoms from the group
consisting of S, N and O, where the ring systems may optionally be
substituted by halogen or by straight-chain or branched alkyl or
alkoxy having in each case up to 4 carbon atoms,
[0119] and
[0120] a radical of the formula PO(OR.sup.10)(OR.sup.11)
[0121] in which
[0122] R.sup.10 and R.sup.11 are identical or different and each
represents hydrogen, straight-chain or branched alkyl having up to
8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms, aryl
having 6 to 10 carbon atoms or benzyl,
[0123] and
[0124] oxycycloalkyl having 3 to 8 ring members or radicals of the
formulae --CON.dbd.C(NH.sub.2).sub.2, --C.dbd.NH(NH.sub.2),
--NH--C(.dbd.NH)NH.sub.2 or (CO).sub.eNR.sup.12R.sup.13
[0125] in which
[0126] e represents a number 0 or 1,
[0127] R.sup.12 and R.sup.13 are identical or different and each
represents hydrogen, straight-chain or branched alkyl having up to
14 carbon atoms or cycloalkyl having 3 to 14 carbon atoms, aryl
having 6 to 10 carbon atoms or a saturated or unsaturated 3- to
10-membered ring having up to 5 heteroatoms from the group
consisting of N, O, S, where the abovementioned radicals may
optionally be substituted by aryl having 6 to 10 carbon atoms,
heterocyclyl, cycloalkyl having 3 to 7 carbon atoms, hydroxyl,
amino or straight-chain or branched alkoxy, acyl or alkoxycarbonyl
having in each case up to 6 carbon atoms,
[0128] and, in the case that e=1,
[0129] R.sup.12 and R.sup.13, together with the nitrogen atom to
which they are attached, may also form a 5- or 6-membered ring
having up to 3 heteroatoms from the group consisting of N, O, S,
which may optionally substituted up to 3 times by hydroxyl, alkoxy
or alkyl having in each case up to 8 carbon atoms,
[0130] and, in the case that e=0,
[0131] R.sup.12 and R.sup.13 may also represent straight-chain,
branched or cyclic acyl having up to 14 carbon atoms, hydroxyalkyl,
straight-chain or branched alkoxycarbonyl or acyloxyalkyl having in
each case up to 6 carbon atoms, or a radical of the formula
--SO.sub.2R.sup.14
[0132] in which
[0133] R.sup.14 represents straight-chain or branched alkyl having
up to 4 carbon atoms,
[0134] and/or
[0135] R.sup.12 and R.sup.13 also represent radicals of the
formulae 7
[0136] in which
[0137] R.sup.15-R.sup.16 and R.sup.18-R.sup.31 are identical or
different and each represents hydrogen or straight-chain or
branched alkyl having up to 4 carbon atoms,
[0138] g represents a number 0, 1 or 2,
[0139] and
[0140] R.sup.17 represents phenyl, straight-chain or branched alkyl
having up to 6 carbon atoms or cycloalkyl having 3 to 8 carbon
atoms,
[0141] with the proviso that, if e=0, R.sup.12 and R.sup.13 do not
simultaneously represent hydrogen,
[0142] or
[0143] R.sup.1 represents a purine radical which may optionally be
substituted up to three times by halogen, azido, cyano, hydroxyl,
amino, monoalkylamino having up to 5 carbon atoms, dialkylamino
having in each case up to 5 carbon atoms, alkyl having up to 5
carbon atoms and/or alkoxy having up to 5 carbon atoms,
[0144] R.sup.2 and R.sup.3, together with the double bond, form a
fused pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl ring,
[0145] which are optionally substituted up to 2 times by identical
or different substituents from the group consisting of formyl,
carboxyl, hydroxyl, mercaptyl, straight-chain or branched acyl,
alkylthio or alkoxycarbonyl having in each case up to 5 carbon
atoms, nitro, cyano, azido, fluorine, chlorine, bromine or
straight-chain or branched alkyl or alkoxy having in each case up
to 5 carbon atoms which for its part may be substituted by
hydroxyl, amino, carboxyl, straight-chain or branched acyl, alkoxy
or alkoxycarbonyl having in each case up to 4 carbon atoms,
[0146] and/or
[0147] the abovementioned heterocyclic rings are optionally
substituted by a group of the formula --NR.sup.32R.sup.33
[0148] in which
[0149] R.sup.32 and R.sup.33 are identical or different and
represent hydrogen or straight-chain or branched alkyl having up to
4 carbon atoms
[0150] or
[0151] R.sup.32 represents hydrogen
[0152] and
[0153] R.sup.33 represents formyl
[0154] and/or the abovementioned fused pyridyl, pyrimidinyl,
pyrazinyl or pyridazinyl rings are optionally substituted by phenyl
which for its part may be substituted by fluorine, chlorine,
bromine or by straight-chain or branched alkyl or alkoxy having in
each case up to 4 carbon atoms,
[0155] A represents thienyl, tetrahydropyranyl, tetrahydrofuranyl,
phenyl, morpholinyl, pyrimidyl, pyrazinyl, pyridazinyl or pyridyl
which are optionally substituted up to 2 times by identical or
different substituents from the group consisting of hydroxyl,
formyl, carboxyl, straight-chain or branched acyl, alkylthio,
alkyloxyacyl, alkoxy or alkoxycarbonyl having in each case up to 4
carbon atoms, fluorine, chlorine and bromine,
[0156] and their isomeric forms and salts.
[0157] Particular preference according to the invention is given to
compounds of the general formula (I) according to claim 1 in
which
[0158] R.sup.1 represents a pyrimidine radical
[0159] which is optionally substituted up to 2 times by identical
or different radicals from the group (i) consisting of
[0160] hydrogen, amino, hydroxyl, alkoxy or alkoxycarbonyl having
in each case up to 3 carbon atoms, cyano or halogen,
[0161] and which is substituted by at least one radical from the
group (ii) consisting of
[0162] a 5- to 6-membered ring which may be saturated, unsaturated
or partially unsaturated, which contains 1 to 3 heteroatoms from
the group consisting of N, O, S, SO, SO.sub.2 and which may also be
attached via N, imidazolyl, imidazolinyl, imidazolidinyl,
morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, triazolyl,
pyrrolyl and thiomorpholinyl being particularly preferred,
[0163] and which is optionally mono- or polysubstituted by a
5-membered ring which contains two oxygen atoms as ring members and
which forms, with the 3- to 8-membered ring, a bicyclic unit or a
spiro unit, such as, for example, a 1,4-dioxa-8-azaspiro[4.5]decane
or 1.5-dioxa-9-azaspiro[5.- 5]undecane radical, and/or by hydroxyl,
cyano, straight-chain or branched alkyl, acyl or alkoxycarbonyl
having in each case up to 3 carbon atoms, where alkyl, acyl and
alkoxycarbonyl may be substituted by hydroxyl, amino, halogen,
carboxyl, straight-chain or branched acyl or alkoxy having in each
case up to 3 carbon atoms,
[0164] and
[0165] a tolyl radical,
[0166] and
[0167] C.sub.7-alkyl which is optionally substituted by cyano,
[0168] and
[0169] (C.sub.1-C.sub.5)alkyl, which is 1- to 3-times substituted
by halogen(s), cyano, aryl and acyloxy,
[0170] and
[0171] --NO or radicals of the formula --S(O).sub.dR.sup.9,
[0172] in which
[0173] d represents a number 1 or 2,
[0174] R.sup.9 represents straight-chain or branched alkyl having 1
to 4 carbon atoms, aryl having 6 carbon atoms or thienyl,
[0175] and
[0176] a radical of the formula PO(OR.sup.10)(OR.sup.11),
[0177] in which
[0178] R.sup.10 and R.sup.11 are identical or different and each
represents straight-chain or branched alkyl having up to 3 carbon
atoms,
[0179] and
[0180] radicals of the formulae --NH--C(.dbd.NH)NH.sub.2 and
(CO).sub.eNR.sup.12R.sup.13
[0181] in which
[0182] e represents a number 0 or 1,
[0183] R.sup.12 and R.sup.13 are identical or different and each
represents hydrogen, straight-chain or branched alkyl having up to
4 carbon atoms or cycloalkyl having 3 carbon atoms, where the
abovementioned radicals may optionally be substituted by aryl
having 6 carbon atoms, furyl, cycloalkyl having 3 carbon atoms,
hydroxyl, straight-chain alkoxy having up to 2 carbon atoms,
[0184] and, in the case that e=1,
[0185] R.sup.12 and R.sup.13, together with the nitrogen atom to
which they are attached, may also form a 5- or 6-membered ring
having up to 2 heteroatoms from the group consisting of N, O, S
which may optionally be substituted up to 2 times by hydroxyl or
methyl,
[0186] and, in the case that e=0,
[0187] R.sup.12 and R.sup.13may also represent straight-chain acyl
having up to 14 carbon atoms [lacuna] having up to 2 carbon
atoms,
[0188] and/or
[0189] R.sup.12 and R.sup.13 also represent a radical of the
formula 8
[0190] with the proviso that in the case that e=0, R.sup.12 and
R.sup.13 do not simultaneously represent hydrogen,
[0191] or
[0192] R.sup.1 represents a purine radical which may optionally be
substituted up to two times by halogen, azido, amino,
monoalkylamino having up to 4 carbon atoms and/or methyl,
[0193] R.sup.2 and R.sup.3, together with the double bond, form a
pyridyl or pyrimidinyl ring,
[0194] A represents phenyl or pyrimidyl, which are optionally
substituted by fluorine, chlorine or bromine,
[0195] and their isomeric forms and salts.
[0196] Particular preference according to the invention is given to
compounds of the general formula (I) in which
[0197] R.sup.1 represents a radical of the formula 9
[0198] in which
[0199] R' represents NH.sub.2,
[0200] R" represents optionally substituted morpholinyl,
piperidinyl, piperazinyl, pyrrolidinyl, triazolyl or
thiomorpholinyl
[0201] and
[0202] R'" represents hydrogen or NH.sub.2.
[0203] Very particular preference is given here to compounds in
which R" represents morpholinyl.
[0204] The compounds of the general formula (I) according to the
invention may also be present in the form of their salts. In
general, salts with organic or inorganic bases or acids may be
mentioned here.
[0205] In the context of the present invention, preference is given
to physiologically acceptable salts. Physiologically acceptable
salts of the compounds according to the invention may be salts of
the substances according to the invention with mineral acids,
carboxylic acids or sulphonic acids. Particular preference is
given, for example, to salts with hydrochloric acid, hydrobromic
acid, sulphuric acid, phosphoric acid, methanesulphonic acid,
ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid,
naphthalenedispulphonic acid, acetic acid, propionic acid, lactic
acid, tartaric acid, citric acid, fumaric acid, maleic acid or
benzoic acid.
[0206] Physiologically acceptable salts may also be the metal or
ammonium salts of the compounds according to the invention which
have a free carboxyl group. Particular preference is given, for
example, to sodium, potassium, magnesium or calcium salts, and to
ammonium salts which are derived from ammonia, or organic amines,
such as, for example, ethylamine, di- or triethylamine, di- or
triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine,
lysine or ethylenediamine.
[0207] The compounds according to the invention may exist in
stereoisomeric forms which are either like image and mirror image
(enantiomers) or which are not like image and mirror image
(diastereomers). The invention relates both to the enantiomers or
diastereomers and to their respective mixtures. The racemates, like
the diastereomers, can be separated into stereoisomerically uniform
components in a known manner.
[0208] In the context of the present invention, the substituents
have, unless indicated otherwise, generally the following
meanings:
[0209] Alkyl generally represents a straight-chain or branched
hydrocarbon radical having 1 to 20 carbon atoms. Examples which may
be mentioned are methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
pentyl, isopentyl, hexyl, isohexyl, heptyl, isoheptyl, octyl and
isooctyl, nonyl, decyl, dodecyl, eicosyl.
[0210] Alkenyl generally represents a straight-chain or branched
hydrocarbon radical having 2 to 20 carbon atoms and one or more,
preferably one or two, double bonds.
[0211] Examples which may be mentioned are allyl, propenyl,
isopropenyl, butenyl, isobutenyl, pentenyl, isopentenyl, hexenyl,
isohexenyl, heptenyl, isoheptenyl, octenyl, isooctenyl.
[0212] Alkinyl generally represents a straight-chain or branched
hydrocarbon radical having 2 to 20 carbon atoms and one or more,
preferably one or two, triple bonds. Examples which may be
mentioned are ethinyl, 2-butinyl, 2-pentinyl and 2-hexinyl.
[0213] Acyl generally represents straight-chain or branched lower
alkyl having 1 to 9 carbon atoms which is attached via a carbonyl
group. Examples which may be mentioned are: acetyl, ethylcarbonyl,
propylcarbonyl, isopropylcarbonyl, butylcarbonyl and
isobutylcarbonyl.
[0214] Alkoxy generally represents a straight-chain or branched
hydrocarbon radical having 1 to 14 carbon atoms which is attached
via an oxygen atom. Examples which may be mentioned are methoxy,
ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy isopentoxy,
hexoxy, isohexoxy, heptoxy, isoheptoxy, octoxy or isooctoxy. The
terms "alkoxy" and "alkyloxy" are used synonymously.
[0215] Alkoxyalkyl generally represents an alkyl radical having up
to 8 carbon atoms which is substituted by an alkoxy radical having
up to 8 carbon atoms.
[0216] Alkoxycarbonyl can be depicted, for example, by the formula
10
[0217] Alkyl here generally represents a straight-chain or branched
hydrocarbon radical having 1 to 13 carbon atoms. The following
alkoxycarbonyl radicals may be mentioned as examples:
methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
isopropoxycarbonyl, butoxycarbonyl or isobutoxycarbonyl.
[0218] Cycloalkyl generally represents a cyclic hydrocarbon radical
having 3 to 8 carbon atoms. Preference is given to cyclopropyl,
cyclopentyl and cyclohexyl. Examples which may be mentioned are
cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
[0219] Cycloalkoxy represents, in the context of the invention, an
alkoxy radical whose hydrocarbon radical is a cycloalkyl radical.
The cycloalkyl radical generally has up to 8 carbon atoms. Examples
which may be mentioned are: cyclopropyloxy and cyclohexyloxy. The
terms "cycloalkoxy" and "cycloalkyloxy" are used synonymously.
[0220] Aryl generally represents an aromatic radical having 6 to 10
carbon atoms. Preferred aryl radicals are phenyl and naphthyl.
[0221] Halogen represents, in the context of the invention,
fluorine, chlorine, bromine and iodine.
[0222] Heterocycle represents, in the context of the invention, a
saturated, unsaturated or aromatic 3- to 10-membered, for example
5- or 6-membered, heterocycle which may contain up to 3 heteroatoms
from the group consisting of S, N and O and which, in the case of a
nitrogen atom, may also be attached via this nitrogen atom.
Examples which may be mentioned are: oxadiazolyl, thiadiazolyl,
pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl,
furyl, pyrrolyl, pyrrolidinyl, piperazinyl, tetrahydropyranyl,
tetrahydrofuranyl, 1,2,3-triazolyl, thiazolyl, oxazolyl,
imidazolyl, morpholinyl or piperidyl. Preference is given to
thiazolyl, furyl, oxazolyl, pyrazolyl, triazolyl, pyridyl,
pyrimidinyl, pyridazinyl and tetrahydropyranyl. The term
"heteroaryl" (or "hetaryl") represents an aromatic heterocyclic
radical.
[0223] The invention furthermore provides a process for preparing
compounds of the general formula (I) where, depending on the
various meanings of the heterocycles listed above under R.sup.2 and
R.sup.3,
[0224] [A] compounds of the general formula (II)
R.sup.1--D (II),
[0225] in which
[0226] R.sup.1 is as defined above
[0227] and
[0228] D represents radicals of the formulae 11
[0229] in which
[0230] R.sup.38 represents C.sub.1-C.sub.4-alkyl
[0231] are converted, by reaction with compounds of the general
formula (III)
A--CH.sub.2--NH--NH.sub.2 (III)
[0232] in which
[0233] A is as defined above
[0234] in inert solvents, if appropriate in the presence of a base,
into the compounds of the general formula (I) or (IVa) 12
[0235] in which
[0236] A and R.sup.1 are each as defined above,
[0237] and, in the case of the compounds of the general formula
(IVa), are subsequently cyclized with carboxylic acids, nitrites,
formamides or guanidium salts,
[0238] and, in the case of the compounds of the general formula
(IV), are cyclized with 1,3-dicarbonyl derivatives, their salts,
tautomers, enol ethers or enamines, in the presence of acids and,
if appropriate, under microwave irradiation,
[0239] or
[0240] [B] in the case that R.sup.2 and R.sup.3 together form a
pyrazine ring, compounds of the general formula (IV) are initially
converted by nitrosation into the compounds of the general formula
(V) 13
[0241] in which
[0242] A and R.sup.1 are each as defined above,
[0243] in a second step, the compounds of the general formula (VI)
14
[0244] in which
[0245] A and R.sup.1 are each as defined above
[0246] are prepared by a reduction,
[0247] and these are subsequently cyclized with 1,2-dicarbonyl
compounds, preferably aqueous glyoxal solution,
[0248] or
[0249] [C] compounds of the general formula (VII) 15
[0250] in which
[0251] A.sup.1, R.sup.2 and R.sup.3 are each as defined above
[0252] and
[0253] L represents a radical of the formula
--Sn.sup.39R.sup.40R.sup.41, ZnR.sup.42, iodine, bromine or
triflate
[0254] in which
[0255] R.sup.39, R.sup.40 and R.sup.41 are identical or different
and each represents straight-chain or branched alkyl having up to 4
carbon atoms
[0256] and
[0257] R.sup.42 represents halogen
[0258] are reacted with compounds of the general formula (VIII)
R.sup.1--T (VIII),
[0259] in which
[0260] R.sup.1 is as defined above
[0261] and
[0262] in the case that L=SnR.sup.39R.sup.40R.sup.41 or
ZnR.sup.42,
[0263] T represents triflate or represents halogen, preferably
bromine
[0264] and,
[0265] in the case that L=iodine, bromine or triflate,
[0266] T represents a radical of the formula
SnR.sup.39'R.sup.40'R.sup.41'- , ZnR.sup.42' or
BR.sup.43'R.sup.44'
[0267] in which
[0268] R.sup.39', R.sup.40', R.sup.41' and R.sup.42' have the
meanings of R.sup.39, R.sup.40, R.sup.41 and R.sup.42 given above
and are identical to or different from them,
[0269] R.sup.43' and R.sup.44' are identical or different and each
represents hydroxyl, aryloxy having 6 to 10 carbon atoms or
straight-chain or branched alkyl or alkoxy having in each case up
to 5 carbon atoms, or together form a 5- or 6-membered carbocyclic
ring
[0270] in a palladium-catalysed reaction in inert solvents, if
appropriate in the presence of a base,
[0271] or
[0272] [D] in the case that R.sup.1 represents an optionally
substituted pyrimidine radical, amidines of the general formula
(IX) 16
[0273] in which
[0274] A, R.sup.2 and R.sup.3 are each as defined above
[0275] are reacted, for example, with compounds of the general
formula (X), (Xa), (Xb) or (Xc) 17
[0276] in which
[0277] R.sup.1' represents the optionally substituted cycloalkyl
radical listed above under R.sup.1;
[0278] Alk represents straight-chain or branched alkyl having up to
8 carbon atoms, preferably up to 4 carbon atoms;
[0279] and
[0280] Z represents an NH.sub.2 group, a monoalkylamino group
having up to 7 carbon atoms, a dialkylamino group having up to 7
carbon atoms, a piperidinyl or morpholinyl radical which is
attached via the nitrogen, hydroxyl, alkoxy having up to 7 carbon
atoms, acyloxy having up to 7 carbon atoms or aroyloxy having 6 to
10 carbon atoms,
[0281] and, in the case of the groups --S(O).sub.cNR.sup.6R.sup.7
and --S(O).sub.cNR.sup.6'R.sup.7', starting from the unsubstituted
compounds of the general formula (I), reacted initially with
thionyl chloride and, in a second step, with the appropriate
amines
[0282] and, if appropriate, the substituents listed under X, Y,
R.sup.1, R.sup.2, R.sup.3 and/or R.sup.4 are modified or introduced
by customary methods, preferably by acylation of free amino groups
or hydroxyl groups, chlorination, catalytic hydrogenation,
reduction, oxidation, removal of protective groups and/or
nucleophilic substitution.
[0283] By way of example, the process according to the invention
can be illustrated by the following equations: 1819
[0284] The heterocycles listed under R.sup.2 and R.sup.3 can also
be introduced by reacting the appropriately substituted compounds
according to other known heterocyclic syntheses.
[0285] Suitable solvents for the individual steps of process [A]
and [B] are inert organic solvents which do not change under the
reaction conditions. These include ethers, such as diethyl ether or
tetrahydrofuran, DME, dioxane, alcohols, such as methanol and
ethanol, halogenated hydrocarbons, such as dichloromethane,
trichloromethane, carbon tetrachloride, 1,2-dichloroethane,
trichloroethane, tetrachloroethane, 1,2-dichloroethane or
trichloroethylene, hydrocarbons, such as benzene, xylene, toluene,
hexane, cyclohexane, or mineral oil fractions, nitromethane,
dimethylformamide, acetone, acetonitrile or hexamethylphosphoric
triamide. It is also possible to use mixtures of the solvents.
Particular preference is given to tetrahydrofuran,
dimethylformamide, toluene, dioxane or dimethoxyethane.
[0286] Bases which are suitable for use in the processes according
to the invention are, in general, inorganic or organic bases. These
preferably include alkali metal hydroxides, such as, for example,
sodium hydroxide or potassium hydroxide, alkaline earth metal
hydroxides, such as, for example, 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
methoxide or potassium methoxide, sodium ethoxide or potassium
ethoxide or potassium tert-butoxide, or organic amines
(trialkyl(C.sub.1-C.sub.6)-amines), such as triethylamine, or
heterocycles, such as 1,4-diazabicyclo[2.2.2]octane (DABCO),
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), pyridine,
diaminopyridine, methylpiperidine or morpholine. It is also
possible to use alkali metals, such as sodium, and their hydrides,
such as sodium hydride, as bases. Preference is given to sodium
carbonate and potassium carbonate, triethylamine and sodium
hydride.
[0287] When reacting the compounds of the formula (II) with the
compounds of the formula (III), the base is employed in an amount
of 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).
[0288] The reaction of the compounds of the formula (II) with the
compounds of the formula (III) is generally carried out in a
temperature range of from 0.degree. C. to 150.degree. C.,
preferably from +20.degree. C. to +110.degree. C.
[0289] This reaction can be carried out at atmospheric pressure or
at elevated or reduced pressure (for example from 0.5 to 5 bar). In
general, the reaction is carried out at atmospheric pressure.
[0290] Suitable acids for the cyclization reactions which may have
to be carried out in the processes according to the invention are,
in general, protic acids. These preferably include inorganic acids,
such as, for example, hydrochloric acid or sulphuric acid, or
organic carboxylic acids having 1-6 C atoms which are optionally
substituted by fluorine, chlorine and/or bromine, such as, for
example, acetic acid, trifluoroacetic acid, trichloroacetic acid or
propionic acid, or sulphonic acids having C.sub.1-C.sub.4-alkyl
radicals or aryl radicals, such as, for example, methanesulphonic
acid, ethanesulphonic acid, benzenesulphonic acid or
toluenesulphonic acid.
[0291] The catalytic hydrogenation reactions which may have to be
carried out in the processes according to the invention can
generally be carried out with hydrogen in water or in inert organic
solvents, such as alcohols, ethers or halogenated hydrocarbons, or
mixtures thereof, using catalysts such as raney nickel, palladium,
palladium on animal charcoal or platinum, or using hydrides or
boranes in inert solvents, if appropriate in the presence of a
catalyst.
[0292] The chlorination reactions which may have to be carried out
in the processes according to the invention are generally carried
out using the customary chlorinating agents, such as, for example,
PCl.sub.3, PCl.sub.5, POCl.sub.3 or elemental chlorine. In the
context of the invention, preference is given to POCl.sub.3.
[0293] The acylations of free amino groups or hydroxyl groups which
may have to be carried out in the processes according to the
invention can be carried out by customary methods which are known
to the person skilled in the art. It is possible, for example, to
convert appropriate free amino groups or hydroxyl groups by
reaction with an acyl halide, preferably an acyl chloride, or an
acetic anhydride, in the presence of a base, such as, for example,
sodium hydride, pyridine or dimethylaminopyridine in a solvent such
as tetrahydrofuran or dichloromethane into the respective amides or
esters, or to convert them into the respective sulphonamides or
sulphonic esters by reaction with a sulphonyl halide, preferably a
sulphonyl chloride.
[0294] The oxidations of thioether groups to sulphoxide groups or
sulphone groups which may have to be carried out in the processes
according to the invention can be carried out by customary methods
known to the person skilled in the art. Such oxidations can, for
example, be carried out using m-chloroperoxybenzoic acid (MCPBA) in
a solvent such as dichloromethane.
[0295] The nucleophilic substitutions and Vilsmeier reactions which
may have to be carried out in the processes according to the
invention are carried out by customary methods known to the person
skilled in the art.
[0296] The nitrosation of the compounds of the formula (IV) to the
compounds of the formula (V), which constitutes the first step of
the process [B], can be carried out in accordance with the
procedure of P. G. Baraldi et al., Synthesis 1984, 148.
[0297] The reductions which may have to be carried out in the
processes according to the invention are generally carried out
using reducing agents, preferably those which are suitable for
reducing carbonyl to hydroxyl compounds. Particularly suitable here
is the reduction with metal hydrides or complex metal hydrides in
inert solvents, if appropriate in the presence of a trialkylborane.
Preference is given to reduction with complex metal hydrides, such
as, for example, lithium borohydride, sodium borohydride, potassium
borohydride, zinc borohydride, lithium trialkyl borohydride,
diisobutylaluminium hydride or lithium aluminium hydride. The
reduction is very particularly preferably carried out using
diisobutylaluminium hydride and sodium borohydride.
[0298] Here, the reducing agent is generally employed in an amount
of from 1 mol to 6 mol, preferably from 1 mol to 4 mol, based on 1
mol of the compounds to be reduced.
[0299] The reductions which may have to be carried out in the
processes according to the invention are generally carried out in a
temperature range of from -78.degree. C. to +50.degree. C.,
preferably from -78.degree. C. to 0.degree. C. in the case of DIBAH
and 0.degree. C. to room temperature in the case of NaBH.sub.4.
[0300] The reductions which may have to be carried out in the
processes according to the invention are generally carried out at
atmospheric pressure. However, it is also possible to operate under
elevated or reduced pressure.
[0301] The compounds of the general formulae (II) and (III) are
known per se, or they can be prepared by customary methods (cf.: J.
Hromatha et al., Monatsh. Chem. 1976, 107, 233).
[0302] Some of the compounds of the general formulae (IV), (IVa),
(V) and (VI) are known, and they can be prepared as described
above.
[0303] Suitable solvents for the process [C] are inert organic
solvents which do not change under the reaction conditions. These
include ethers, such as diethyl ether or tetrahydrofuran, DME,
dioxane, halogenated hydrocarbons, such as dichloromethane,
trichloromethane, carbon tetrachloride, 1,2-dichloroethane,
trichloroethane, tetrachloroethane, 1,2-dichloroethylene or
trichloroethylene, hydrocarbons, such as benzene, xylene, toluene,
hexane, cyclohexane, or mineral oil fractions, nitromethane,
dimethylformanide, acetone, acetonitrile or hexamethylphosphoric
triamide. It is also possible to use mixtures of the solvents.
Particular preference is given to tetrahydrofuran,
dimethylformamide, toluene, dioxane or dimethoxyethane.
[0304] The reaction of the compounds of the formula (VII) with the
compounds of the formula (VIII) is generally carried out in a
temperature range of from 0.degree. C. to 150.degree. C.,
preferably from +20.degree. C. to +110.degree. C.
[0305] This reaction can be carried out at atmospheric pressure or
at elevated or reduced pressure (for example from 0.5 to 5 bar). In
general, the reaction is carried out at atmospheric pressure.
[0306] Suitable palladium compounds in the context of the present
invention are, in general,
PdCl.sub.2(P(C.sub.6H.sub.5).sub.3).sub.2,
palladium-bis-dibenzylideneacetone (Pd(dba).sub.2),
[1,1'-bis-(diphenylphosphino)ferrocene]-palladium(II) chloride
(Pd(dppf)Cl.sub.2) or Pd(P(C.sub.6H.sub.5).sub.3).sub.4. Preference
is given to Pd(P(C.sub.6H.sub.5).sub.3).sub.4.
[0307] The compounds of the general formula (VI) are known per se,
or they can be prepared by customary methods (cf., for example K.
Kirschke in: Houben-Weyl, Methoden der organischen Chemie,
Thieme-Verlag Stuttgart, 4th Ed., volume E8b, part 2, 399-763; in
particular with respect to pyrazolopyridines: C. R. Hardy in A. R.
Katritzky (Ed.), Adv. Het. Chem. 1984, 36, 343-409; in particular
with respect to pyrazolopyrimidines: M. H. Elgnadi et al., Adv.
Het. Chem. 1987, 41, 319-376). The preparation of the corresponding
halogenopyrozolo[3,4-b]pyrinmidines and organotin
pyrazolo[3,4-b]pyrimidines of the formula (VII) is described in WO
98/23619 and can also be carried out analogously for the
corresponding triflate and organotin compounds of the formula
(VII).
[0308] The compounds of the general formula (VIII) are known and
can be prepared by customary methods (cf., for example, M. G.
Hoffmann et al. in: Houben-Weyl, Methoden der organischen Chemie,
4th ed., volume E9b, part 1, pp. 1-249; A. Weissenberger et al.,
The Chemistry of heterocyclic compounds--pyrimidines, 1962, 16;
ibid 1970, 16, suppl. 1, ibid 1985, 16, suppl. 2; ibid 1994,
52).
[0309] The process [D] is carried out in a temperature range of
from 80.degree. C. to 120.degree. C., preferably at from
100.degree. C. to 110.degree. C., or under reflux.
[0310] Suitable solvents are, for example, the reagents of the
general formula (X), (Xa), (Xb) or (Xc). However, the reaction can
also be carried out in other suitable solvents, such as, for
example, toluene, methanol or dichloromethane. Low-boiling
solvents, such as, for example, dichloromethane, can be distilled
off during the course of the reaction.
[0311] The process [D] can be carried out at atmospheric pressure
or at elevated or reduced pressure (for example from 0.5 to 5 bar).
In general, the process is carried out at atmospheric pressure.
[0312] Here, the reaction can either proceed in one step or via
open-chain compounds such as, for example, 20
[0313] The reaction can be carried out under reduced pressure. It
can proceed both with or without addition of the abovementioned
solvents, acid or base.
[0314] The amidines of the general formula (IX) can be prepared by
reacting the compounds of the general formula (XI) 21
[0315] in which
[0316] A, R.sup.2 and R.sup.3 are each as defined above
[0317] initially in ethers with trifluoroacetic anhydride (TFAA)
and in the presence of bases to give the compound of the general
formula (XII) 22
[0318] in which
[0319] A, R.sup.2 and R.sup.3 are each as defined above,
[0320] subsequently preparing the compounds of the general formula
(XIII) 23
[0321] in which
[0322] A, R.sup.2 and R.sup.3 are each as defined above
[0323] using sodium methoxide, in a next step converting these
compounds by reaction with NH.sub.4Cl and glacial acetic acid in
alcohols into the corresponding amidine HCl salt of the general
formula (XIV) 24
[0324] in which
[0325] A, R.sup.2 and R.sup.3 are each as defined above
[0326] and, in a last step, reacting with bases, preferably sodium
carbonate, or alkali metal alkoxide, such as sodium ethoxide.
[0327] Suitable solvents for reacting the compounds of the general
formula (XI) to give the compounds of the formula (XII) are ethers,
such as diethyl ether or tetrahydrofuran, dimethylformamide and
dioxane; preference is given to tetrahydrofuran.
[0328] Suitable for use as bases here are organic amines
(trialkyl(C.sub.1-C.sub.6)-amines) such as triethylamine, or
heterocycles, such as 1,4-diazabicyclo[2.2.2]octane (DABCO),
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), pyridine,
dimethylaminopyridine, methylpiperidine or morpholine. Preference
is given to pyridine.
[0329] The reaction is carried out in a temperature range of from
0.degree. C. to 40.degree. C., preferably at room temperature.
[0330] The reaction can be carried out at atmospheric pressure or
at elevated or reduced pressure (for example from 0.5 to 5 bar). In
general, the reaction is carried out at atmospheric pressure.
[0331] The amide (XI) can be prepared, for example, by hydrolysing
an appropriate ester as starting material with a base to give the
acid, converting the acid into the acyl chloride by customary
methods, for example using SOCl.sub.2 or POCl.sub.3, followed by
reaction with ammonia.
[0332] The elimination of water from the amide (XI) to given the
nitrile (XII) can be carried out with any customary dehydrating
agent. Preference according to the invention is given to
trifluoroacetic anhydride (TFAA).
[0333] The nitrile of the formula (XII) can be converted into the
iminoether of the formula (XIII) both under acidic conditions, such
as, for example, with HCl/alcohol mixtures, and under basic
conditions, such as, for example, with methanol/sodium methoxide.
It is generally carried out at from 0.degree. C. to 40.degree. C.,
for example at room temperature.
[0334] Suitable solvents for converting the compounds of the
general formula (XIII) into the compounds of the formula (XIV) are
alcohols, such as methanol or ethanol. Preference is given to
methanol.
[0335] The reaction is carried out in a temperature range of from
0.degree. C. to 40.degree. C., preferably at room temperature.
[0336] The reaction can be carried out under atmospheric pressure
or under elevated or reduced pressure (for example from 0.5 to 5
bar). In general, the reaction is carried out at atmospheric
pressure.
[0337] Suitable bases for liberating the compounds of the general
formula (IX) from compounds of the general formula (XIV) are
inorganic or organic bases. These 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 metal carbonates, such as calcium carbonate, and
alkali metal alkoxides, such as sodium methoxide. Preference is
given to sodium carbonate and sodium methoxide.
[0338] The pyrimidine ring is prepared by customary methods (cf.,
for example, M. G. Hoffmann et al. in: Houben-Weyl, Methoden der
organischen Chemie, 4th ed., volume E9b, part 1, pp. 1-249; A.
Weissenberger et al., The Chemistry of heterocyclic compounds -
pyrimidines, 1962, 16; ibid 1970, 16, suppl. 1, ibid 1985, 16,
suppl. 2; ibid 1994, 52).
[0339] Here, the iminoethers of the formula (XIII) can be used as
starting materials and be reacted, for example, with a suitable
enamine. However, it is also possible to convert the iminoether
first, using ammonia or its salts, into a corresponding amidine and
to react this either as the free base (IX) or as a salt (XIV) with
enamines, acetals, enol ethers, aldehydes, enolates, malononitrile
esters or malonodinitriles.
[0340] The enamines which may have to be used in this reaction 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, for example,
bis(dimethylamino)-tert-butoxymethane,
dialkoxy-dialkylamino-methanes.
[0341] The compounds of the general formula (XI) can be prepared by
converting the compounds of the general formula (XV) 25
[0342] with the compounds of the general formula (XVI)
A--CH.sub.2--NH--NH.sub.2 (XVI)
[0343] in ethers, preferably dioxane, and trifluoroacetic acid into
the compounds of the general formula (XVII) 26
[0344] subsequently preparing, by reaction with the compounds of
the general formula (XVIII)
Z--CH.dbd.CH--CHO (XVIII)
[0345] in which
[0346] Z is as defined above, in particular --N(CH.sub.3).sub.2
[0347] in inert solvents, preferably dioxane, the compounds of the
general formula (XIX) 27
[0348] followed in a last step by treatment with ammonia in
methanol.
[0349] Instead of the sodium salt of the enolate (XV), it is also
possible to employ enol ethers, ketones or enamines.
[0350] If appropriate, the reaction of the compounds of the general
formulae (XV) and (XVI) to give (XVII) can also be carried out via
intermediates of the formulae (A) and (B), 28
[0351] at room temperature.
[0352] The compounds of the general formula (X) can be prepared,
for example, by reacting the compounds of the formula (XX) or
(XXa)
[Alk.sub.2N].sub.2--CH--OAlk' (XX)
Alk.sub.2N--CH--[OAlk'].sub.2 (XXa)
[0353] in which
[0354] Alk and Alk' are identical or different and each represent
straight-chain or branched alkyl having up to 5 carbon atoms
[0355] with compounds of the formula (XXI)
R.sup.1'--CH.sub.2--CN (XXI)
[0356] in which
[0357] R.sup.1' represents the cycloalkyl radical listed above
under R.sup.1.
[0358] The compounds of the general formulae (XX), (XXa) and (XXI)
are known, or they can be prepared by customary methods.
[0359] Some of the compounds of the general formulae (XII), (XIII),
(XIV), (XV), (XVII), (XVIII) and (XIX) are novel, and they can be
prepared as described above.
[0360] The pyrimidine radical can also be synthesized with the aid
of the reagent of the formula (Xa) which is accessible, for
example, as follows:
[0361] Compounds of the general formula 29
[0362] in which R.sup.1' is as defined above and Alk represents an
alkyl radical having up to 4 carbon atoms
[0363] are converted, by using ammonia in suitable solvents,
preferably alcohols such as methanol, at temperatures from
0.degree. C. to 40.degree. C., preferably at room temperature, into
compounds of the general formula (XXIII) 30
[0364] in which R.sup.1' is as defined above,
[0365] and these are subsequently reacted by customary methods with
dehydrating agents, such as, for example, Burgess reagent,
POCl.sub.3, P.sub.2O.sub.5, SOCl.sub.2, trifluoroacetic
anhydride/pyridine.
[0366] If Burgess reagent is used, the reaction is preferably
carried out in inert solvents, such as ethers or chlorinated
hydrocarbons. Examples which may be mentioned are dichloromethane
and tetrahydrofuran. Preference is given to using a 1:2 mixture of
the abovementioned solvents. The reaction is carried out at
temperatures from 0.degree. C. to 40.degree. C., preferably at room
temperature.
[0367] The compounds of the formula (XXII) are known and/or
obtainable in a simple manner known to the person skilled in the
art.
[0368] Some of the compounds of the formula (X) undergo keto-enol
tautomerism, for example: 31
[0369] The pyrimidine radical can also be synthesized with the aid
of the reagent of the formula (Xa) which is obtainable, for
example, as follows:
[0370] Compounds of the general formula (XXIIa) 32
[0371] in which
[0372] R.sup.1' is as defined above and
[0373] Alk represents an alkyl radical having up to 4 carbon
atoms
[0374] are converted, using ammonia in suitable solvents,
preferably alcohols such as methanol, at temperatures from
0.degree. C. to 40.degree. C., preferably room temperature, into
compounds of the general formula (XXIIIa) 33
[0375] in which R.sup.1.sup.1 is as defined above,
[0376] and these are subsequently reacted by customary methods with
dehydrating agents, such as, for example, Burgess reagent,
POCl.sub.3, P.sub.2O.sub.5, SOCl.sub.2, trifluoroacetic
anhydride/pyridine.
[0377] If Burgess reagent is used, the reaction is preferably
carried out in inert solvents, such as ethers or chlorinated
hydrocarbons. Examples which may be mentioned are dichloromethane
and tetrahydrofuran. Preference is given to using a 1:2 mixture of
the abovementioned solvents. The reaction is carried out at
temperatures from 0.degree. C. to 40.degree. C., preferably at room
temperature.
[0378] The compounds of the formula (XXIIa) are known and/or
obtainable in a simple manner known to the person skilled in the
art.
[0379] If typical protective groups are employed in the course of
derivatization reaction, their removal is generally carried out in
one of the abovementioned alcohols and/or THF or acetone,
preferably methanol/THF in the presence of hydrochloric acid or
trifluoroacetic acid or toluenesulphonic acid, in a temperature
range of from 0.degree. C. to 70.degree. C., preferably at room
temperature under atmospheric pressure.
[0380] The compounds of the general formula (I) according to the
invention have an unforeseeable, valuable spectrum of
pharmacological action.
[0381] The compounds of the general formula (I) according to the
invention lead to a vasorelaxation, inhibition of platelet
aggregation and to a fall in blood pressure and also to an increase
in coronary blood flow. These actions are mediated via a direct
stimulation of soluble guanylate cyclase and an intracellular cGMP
increase. Additionally, the compounds of the general formula (I)
according to the invention enhance the action of substances which
raise the cGMP level, such as, for example, EDRF
(endothelium-derived relaxing factor), NO donors, protoporphyrin
IX, arachidonic acid or phenylhydrazine derivatives.
[0382] They can therefore be employed in medicaments for the
treatment of cardiovascular disorders, such as, for example, for
the treatment of high blood pressure and cardiac insufficiency,
stable and unstable angina pectoris, peripheral and cardiac
vascular disorders, arrhythmias, for the treatment of
thromboembolic disorders and ischaemias such as myocardial infarct,
stroke, transitory and ischaemic attacks, peripheral circulatory
disorders, prevention of restenoses such as after thrombolysis
therapy, percutaneous translumino angioplastie (PTA), percutaneous
transluminalo coronary angioplasty (PTCA), bypass and also for the
treatment of arterioscleroses, asthmatic disorders and disorders of
the urogenital system such as, for example, prostate hypertrophy,
erectile dysfunction, female sexual dysfunction and
incontinence.
[0383] The compounds of the general formula (I) described in the
present invention are also active compounds for controlling
disorders in the central nervous system which are characterized by
disturbances of the NO/cGMP system. In particular, they are
suitable for eliminating cognitive deficits, for improving learning
and memory performance and for treating 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,
sleeping disorders and sexual dysfunction caused by the central
nervous system, and for regulating pathological eating disorders or
disorders associated with the use of stimulants and drugs.
[0384] Furthermore, the active compounds are also suitable for
regulating cerebral circulation, and they are therefore effective
agents for controlling migraines.
[0385] They are also suitable for the prophylaxis and control of
the sequelae of cerebral infarcts (Apoplexia cerebri) such as
stroke, cerebral ischaemia and skull-brain trauma. The compounds of
the general formula (I) according to the invention can also be
employed for controlling pain.
[0386] Additionally, the compounds according to the invention have
antiinflammatory action and can therefore be employed as
antiinflammatories.
[0387] The invention moreover includes the combination of the
compounds of the general formula (I) according to the invention
with organic nitrates and NO donors.
[0388] Organic nitrates and NO donors in the context of the
invention are, in general, substances which display their
therapeutic action by the release of NO or NO species. Sodium
nitroprusside, glycerol trinitrate, isosorbide dinitrate,
isosorbide mononitrate, molsidomine and SIN-1 are preferred.
[0389] The invention additionally includes the combination with
compounds which inhibit the degradation 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 p. 150 to 155. The action of the compound
according to the invention is potentiated and the desired
pharmacological effect is increased by these inhibitors.
[0390] To determine the cardiovascular action, the following
investigations were carried out: In in vitro investigations on the
isolated enzyme and on cells of vascular origin, the effect on
guanylate cyclase-dependent cGMP formation was tested with and
without NO donor. The anti-aggregatory properties were shown on
human platelets stimulated with collagen. The vasorelaxant action
was determined in rabbit aortal rings preconcentrated with
phenylephrine. The hypotensive action was investigated in
anaesthetized and awake rats.
Stimulation of Recombinant Soluble Guanylate Cyclase In Vitro
[0391] The investigations on the stimulation of recombinant soluble
guanylate cyclase by the compounds according to the invention with
and without NO donor were carried out using the method which is
described in detail in the following literature reference: M.
Hoenicka, E. M. Becker, H. Apeler, T. Sirichoke, H. Schroeder, R.
Gerzer and J.-P. Stasch: Purified soluble guanylate cyclase
expressed in a baculovirus/Sf9 system: stimulation by YC-1, nitric
oxide, and carbon oxide. J. Mol. Med. 77: 14-23 (1999). The results
are shown in FIG. 1.
Stimulation of Soluble Guanylate Cyclase in Primary Endothelial
Cells
[0392] Primary endothelial cells were isolated from pig aortas by
treatment with collagenase soln. The cells were then cultured in
culture medium at 37 C/5% CO.sub.2 until confluence was reached.
For the investigations, the cells were passaged, inoculated into
24-well cell culture plates and subcultured until reaching
confluence (.about.2.times.10.sup.5 cells/well). For the
stimulation of endothelial guanylate cyclase, the culture medium
was aspirated and the cells were washed once with Ringer solution.
After removing the Ringer solution, the cells were incubated for 10
minutes at 37.degree. C./5% CO.sub.2 in stimulation buffer with or
without NO donor (sodium nitroprusside, SNP or DEA/NO 1 .mu.M).
Following this, the test substances (final concentration 1 .mu.M)
were added to the cells by pipette, and they were incubated for a
further 10 minutes. After the incubation time had ended, the buffer
solution was aspirated and cold buffer at 4.degree. C. was added to
the cells. The cells were then lysed at -20.degree. C. for 16
hours. The supernatants containing the intracellular cGMP were then
removed and the cGMP concentration was determined by means of the
cGMP-SPA system (Amersham Buchler, Brunswick). The results are
shown in Tables 1 and 2 below:
1TABLE 1 Stimulation of soluble guanylate cyclase in primary
endothelial cells Increase in the cGMP Example No. concentration
(%) 1 >1000 2 >1000 3 >1000 6 600 13 >1000 14
>1000
[0393]
2TABLE 2 Stimulation of soluble guanylate cyclase in primary
endothelial cells by 3-(4,6-diamino-5-
N-morpholinopyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-
pyrazolo[3,4-b]-pyridine (Ex. 16) Ex. 16 (.mu.M) cGMP (pmol/well) 0
1.7 0.1 5.1 0.3 13.2 1.0 20.8 3.0 34.5 10 47.7
Vasorelaxant Action In Vitro
[0394] Rabbits are anaesthetized by a blow to the neck and
exanguinated. The aorta is removed, freed from adhering tissue,
divided into 1.5 mm wide rings and individually transferred under a
pretension into 5 ml organ baths containing a warm,
carbogen-aerated Krebs-Henseleit solution at 37.degree. C. of the
following composition (mM): NaCl:119; KCl:4.8;
CaCl.sub.2.times.2H.sub.2O:1; MgSO.sub.4.times.7H.sub.2O;1.4;
KH.sub.2PO.sub.4:1.2; NaHCO.sub.3:25; glucose: 10. The
contractility is detected using Statham UC.sub.2 cells, amplified
and digitalized by means of A/D converters (DAS-1802 HC, Keithley
Instruments Munich), and recorded in parallel on linear recorders.
To produce a contraction, phenylephrin is added to the cumulatively
in increasing concentration. After several control cycles, the
substance to be investigated is investigated in each further
passage in increasing dosage in each case, and the height of the
contraction is compared with the height of the contraction achieved
in the last preliminary passage. From this, the concentration which
is necessary in order to reduce the height of the control value by
50% (IC.sub.50) is calculated. The standard administration volume
is 5 .mu.l, and the proportion of DMSO in the bath solution
corresponds to 0.1%. The results are shown in Table 3 below:
3TABLE 3 Vasorelaxant action in vitro Example No. IC.sub.50 [.mu.M]
1 0.23 3 0.38 3 0.4 5 0.24 7 3.4 13 0.41 16 0.2 21 0.67 22 0.68 23
0.54 24 0.35 25 0.79 26 1 27 0.18 28 0.22 31 0.53 32 0.58 33 0.62
35 1.8 71 0.7 73 0.69 77 0.76 78 9.5 79 4.1
Blood Pressure Measurements in Anaesthetized Rats
[0395] Male Wistar rats having a bodyweight of 300-350 g are
anaesthetized 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, H.sub.2O (10%/20%/70%) in a volume of 1
ml/kg. The results are listed in Table 4 below.
4TABLE 4 max. reduction in blood pressure Ex. No. Dose (mg/kg p.o.)
(mm Hg) 16 0.3 21 16 1.0 35
Effect on the Average Blood Pressure of Awake, Spontaneously
Hypertensive Rats
[0396] Continuous measurements of blood pressure over 24 hours were
carried out on spontaneously hypertensive female rats (MOL:SPRD)
having a bodyweight of 200-250 g which were allowed to move around
freely. To this end, pressure monitors (Data Sciences Inc., St.
Paul, Minn., USA) were chronically implanted into the descending
abdominal aorta of the animals, below the kidney artery, and the
attached transmitter was fixed in the abdominal cavity.
[0397] The animals were kept individually in type III cages, which
were positioned on the individual receiver stations, and adapted to
a 12-hour day/night rhythm. Water and feed was available
freely.
[0398] To collect the data, the blood pressure of each rat was
registered every 5 minutes for 10 seconds. In each case, the data
for a period of 15 minutes were collected and the average value was
calculated from these values.
[0399] The compounds to be tested were dissolved in a mixture of
Transcutol (10%), Cremophor (20%), H.sub.2O (70%) and administered
orally by means of a stomach tube in a volume of 2 ml/kg of
bodyweight. The doses tested were between 0.3 and 30 mg/kg of
bodyweight. The results are shown in FIG. 2 (attached).
Inhibition of Platelet Aggregation In Vitro
[0400] To determine the platelet-aggregation, blood from healthy
volunteers of both sexes was used. As an anticoagulant, 9 parts of
blood were 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 citrate/citric acid/glucose). The platelets
were subsequently centrifuged off and resuspended in buffer and
once more centrifuged off. The platelet pellet was suspended in
buffer and mixed with an additional 2 mmol/l of CaCl.sub.2.
[0401] To measure the aggregation, aliquots of the platelet
suspension were incubated with the substance to be tested at
37.degree. C. for 10 min. Aggregation was subsequently induced in
an aggregometer by addition of collagen and determined at
37.degree. C. using the turbidometric method according to Born
(Born, G. V. R., J.Physiol. (London), 168, 178-195, 1963). The
results are shown in Table 5 below.
5 TABLE 5 Ex. No. IC.sub.50 (.mu.M) 16 0.06
Measurement of the Erection-promoting Action of Guanylate Cyclase
Stimulators
[0402] For a complete and lasting erection to occur, the cavernous
arteries and the entire cavernous body architecture, which is
formed by a network of smooth muscle cells and collagen connective
tissue, has to be at maximum dilation so that the corpus cavernosum
can fill completely with blood (Anderson K.-E. and Wagner G.,
"Physiology of Penile Erection." Physiological Reviews 75, 191-236
(1995); Meinhardt W. Kropmann R F, Vermeig P, Lycclama a Nigelholt
and Zwartendijk J. "The Influence of Medication on Erectile
dysfunction." Int. J. of Impotence Res. 9, 17-26 (1997). Relaxation
of smooth muscles is mediated by NO which, in the case of sexual
stimulation, is released by non-adrenergic, non-cholinergic nerve
fibres in the endothelial cells of the blood vessels of the corpus
cavernosum. NO activates guanylate cyclase, and the resulting
increase in cGMP leads to dilation of the smooth muscles of the
corpus cavernosum and consequently to an erection. To test the
efficacy of the substances according to the invention, awake
rabbits were used. The species rabbit was chosen since
neurophysiology, haemodynamic and the control of contraction and
relaxation of the smooth muscles of the corpus cavernosum of rabbit
and man are quite similar (Meyer M F, Taher H., Krah H., Staubesand
J., Becker A J, Kircher M, Mayer B., Jonas U., Forsmann W G., Stief
Ch. G. "Intracarvenous Application of SIN-1 in Rabbit and Man:
Functional and Toxcological Results." Annals Urol. 27, 179-182
(1993); Taub H C, Lerner S E, Melman A, Christ G J "Relationship
between contraction and relaxation in human and rabbit corpus
cavernosum." Urology 42, 698-671, (1993).
[0403] Method:
[0404] Adult male chinchilla rabbits having a weight of 3-5 kg are,
after delivery, adapted for several days in isolation. They have
free access to water and can feed for two hours per day. The
animals are kept in a 10/14 hour day/night rhythm (light switched
on from 8.00 hours onwards). The room temperature is 22-24.degree.
C.
[0405] The animals are weighed directly before the start of the
experiment. For intravenous administration, the substances
according to the invention were dissolved in a mixture of
Transcutol (GATTEFOSSE GmbH ) diluted with 20% Cremophor (BASF) and
water in a ratio of 3/7. Sodium nitroprusside was dissolved in 0.9%
NaCl. The substances were injected at the dosages stated in the
table in a volume of 0.5 ml/kg into the auricular vein. For oral
administration, the test substances were dissolved in a mixture of
glycerol: water: polyethylene glycol 6:10:9.69 and administered at
the dosages stated in the table in a volume of 1 ml/kg using the
stomach tube.
[0406] The effect of guanylate cyclase stimulators is increased by
NO donors. This was demonstrated by additionally administering
sodium nitroprusside.
[0407] The sodium nitroprusside was injected into the auricular
vein at a dosage of 0.2 mg/kg simultaneously with the substance
according to the invention. If the substance according to the
invention was administered orally, the sodium nitroprusside was
injected into the auricular vein of these animals 30 min after the
oral administration. Corresponding controls were carried out using
the solvent and using sodium nitroprusside on its own.
[0408] At rest, the penis of the rabbit is not visible in the pubic
region and is covered completely by the sheath. The erection is
assessed by measuring the length of the protruding penis with a
calliper square. Measurements are carried out 5, 10, 15, 30, 45,
60, 120 and 180 min. after the administration of the substance. The
effect is calculated as the product of the length of the penis
which is not covered by fur in [mm] and the time for which the
erection persists in [min].
[0409] Intravenous injection of sodium nitroprusside causes an
erection which lasts for approximately 10 min. (110
[mm.times.min.]).
[0410] The present invention includes pharmaceutical preparations
which, in addition to non-toxic, inert pharmaceutically acceptable
excipients, contain the compounds of the general formula (I)
according to the invention, and also processes for the production
of these preparations.
[0411] The active compounds can optionally be present in one or
more of the excipients indicated above and also in
microencapsulated form.
[0412] The therapeutically active compounds of the general formula
(I) should be present in the abovementioned pharmaceutical
preparations in a concentration from approximately 0.1 to 99.5,
preferably from approximately 0.5 to 95, % by weight of the total
mixture.
[0413] In addition to the compounds of the general formula (I)
according to the invention, the abovementioned pharmaceutical
preparations can also contain other pharmaceutically active
compounds.
[0414] In general, it has proved advantageous both in human and in
veterinary medicine to administer the active compound(s) according
to the invention in total amounts from approximately 0.5 to
approximately 500, preferably 5 to 100, mg/kg of bodyweight every
24 hours, if appropriate in the form of several individual doses,
to achieve the desired results. An individual dose contains the
active compound(s) according to the invention preferably in amounts
from approximately I to approximately 80, in particular 3 to 30,
mg/kg of bodyweight.
[0415] Below, the present invention is illustrated in more detail
using non-limiting, preferred examples. Unless indicated otherwise,
all amounts given refer to per cent by weight.
EXAMPLES
[0416] Abbreviations:
[0417] RT: Room temperature
[0418] EA: Ethyl acetate
[0419] MCPBA: m-Chloroperoxybenzoic acid
[0420] BABA: n-Butyl acetate/n-butanol/glacial acetic
acid/phosphate buffer pH 6 (50:9:25.15; org. phase)
[0421] Mobile Phases for Thin-layer Chromatography:
6 T1 E1: toluene/ethyl acetate (1:1) T1 EtOH1: toluene-methanol
(1:1) C1 E1: cyclohexane/ethyl acetate (1:1) C1 E2:
cyclohexane/ethyl acetate (1:2)
[0422] Starting Materials:
General Procedure for Preparing 2-substituted
3-dimethylaminoacrylonitrile- s
[0423] 34
[0424] With water-cooling, 50.0 mmol of 2-substituted acetonitrile
derivative are added 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.
7 Sulphones: The precipitate is filtered off with suction and dried
under high vacuum Phosphonic The solution is freed of methanol
initially at 40.degree. C. under esters: 20 mbar using a rotary
evaporator, then at room temperature under high vacuum.
[0425]
8 Ex. No. Starting material Product Yield M.p./NMR 1A 35 36 88%
128.degree. C. 2A 37 38 99% liquid 1H-NMR(400 MHz, CDCl.sub.3),
.delta.=1.34(t, 6H, CH.sub.3), 3.12(s, 3H, NCH.sub.3), 3.31(s, 3H,
NCH.sub.3), 4.07 (m, 4H, CH.sub.2), 7.20 (d, 1H, olefin-CH.
Example 3A
[0426] 3-(Dimethylamino)-2-N-morpholinoacrylonitrile 39
[0427] At 80.degree. C., 8.13 g (64.5 mmol) of
morpholinoacetonitrile and 13.3 ml (64.5 mmol) of
tert-butoxy-bis(dimethylamino)methane were stirred overnight. The
mixture was cooled to room temperature, concentrated using a rotary
evaporator and subsequently distilled under reduced pressure.
[0428] Yield: 11.0 g (94%) (cis and transisomer)
[0429] Boiling point: 119.degree. C./0.008 mbar
Example 4A
[0430] 3-(Dimethylamino)-2-N-thiomorpholinoacrylonitrile 40
[0431] At 80.degree. C., 6.65 g (46.8 mmol) of
N-thiomorpholinoacetonitril- e (Wise, L. D. et al., J.Med.Chem.,
17, 1974, 1232-1234) and 9.70 ml (47.0 mmol) of
tert-butoxy-bis(dimethylamino)methane were stirred overnight. The
mixture was cooled to room temperature, concentrated using a rotary
evaporator and subsequently distilled under reduced pressure.
[0432] Yield: 9.98 g (88% with respect to pure substance, cis and
transisomers)
[0433] Boiling point: 96.degree. C./0.008 mbar
Example 5A
[0434] Ethyl 3-dimethylamino-2-methylsulphonylacrylate 41
[0435] 6.65 g (40 mmol) of ethyl methanesulphonylacetate and 5.72 g
(48 mmol) of N,N-dimethylformamide dimethyl acetal are admixed and
heated at 85.degree. C. overnight.
[0436] The solution is concentrated using a rotary evaporator, and
the solid is comminuted with cyclohexane and filtered off with
suction.
[0437] Yield: 8.36 g (94.5% of theory)
Example 6A
[0438] 2-(4-Methylpiperazino)malonodiamide 42
[0439] 1.00 g (5.52 mmol) of 2-bromomalonodiamide (preparation
analogous to Backes, West and Whiteley, J. Chem. Soc. 1921, 119,
359), 0.61 g (6.10 mmol) of N-methylpiperazine and 1.15 g (8.29
mmol) of potassium carbonate are admixed in 10 ml of acetonitrile,
and the mixture is heated at 50.degree. C. overnight. The mixture
is filtered off and the solid is digested with boiling ethanol and
filtered off with suction. The filtrate is concentrated using a
rotary evaporator, and the crude product is reacted further.
[0440] Yield: 1.14 g (crude yield).
[0441] Rf (SiO.sub.2, BABA): 0.06
Example 7A
[0442] 2-(4-Acetylpiperazino)malonodiamide 43
[0443] 6.16 g (25.8 mmol) of diethyl 2-bromomalonate, 3.63 g (28.3
mmol) of N-acetylpiperazine and 5.34 g (38.6 mmol) of potassium
carbonate are admixed in 100 ml of acetonitrile, and the mixture is
heated at 50.degree. C. for 28 hours. The reaction mixture is
cooled, taken up in 50 ml of ethyl acetate and washed with water.
The organic phase is dried over magnesium sulphate and concentrated
using a rotary evaporator. Yield: 8.75 g. 7 g of the crude product
are dissolved in 70 ml of a solution of ammonia and methanol, and
the mixture is stirred at room temperature for 90 hours. The solid
is filtered off with suction, washed with cold methanol and
dried.
[0444] Yield: 2.76 g (49.6% of theory).
Example 8A
[0445] 2-(4-Methylpiperazine)malonodinitrile 44
[0446] 441 mg (2.04 mmol) of 2-(4-methylpiperazine)malonodiamide
from Example 6A are dissolved in 20 ml of tetrahydrofuran:
dichloromethane (3:1). A total of 1.70 g (7.15 mmol) of Burgess
reagent are added in three identical portions at intervals of 30
minutes. After another 30 minutes, the reaction mixture is
chromatographed directly over silica gel using ethyl acetate as
mobile phase.
[0447] Yield: 233 mg (69.4% of theory).
[0448] Rf (SiO.sub.2, EA): 0.22
[0449] Analogously to Examples 6A to 8A, the following compounds
were prepared:
9 45 Yield (% of theory) starting from Ex. No. R malonodiamide Rf
(SiO.sub.2) 9A 46 80.2 0.71 (EA) 10A 47 38.1 0.66 (EA) 11A 48 36.5
0.69 (EA) 12A 49 81.6 0.74 (EA) 13A 50 73.9 0.69 (EA) 14A 51 42.9
0.32 (EA) 15A 52 35.2 0.65 (EA) 16A 53 52.5 0.32 (EA) 17A 54 47.6
0.70 (EA) 18A 55 13.4 0.68 (EA)
[0450] The preparation of 2-N-morpholinomalonodinitrile,
2-(N,N-dimethylamino)malonodinitrile and
2-(N,N-diethylamino)malonodinitr- ile is carried out according to
H. Gold and O. Bayer, Chem. Ber. 1961, 94, 2594.
[0451] 2-(1,3-thiazol-2-yl)-malononitrile is prepared according to
Yamanaka, H.; Ohba, S.; Sakamoto, T. Heterocycles, 1990, 31,
1115.
Example 19A
[0452] 2-(5-Methyl-1,3,4-thiadiazol-2-yl)-malononitrile 56
[0453] Under argon, 400 mg (10.0 mmol) of sodium hydride (60%
suspension in oil) are suspended at room temperature in 40 ml of
THF. A solution of 661 mg (10.0 mmol) of malonodinitrile in 10 ml
of THF is added dropwise, and the reaction mixture is stirred for
15 min. A solution of 891 mg (5.0 mmol) of
2-methyl-5-methylsulphonyl-1,3,4-thiadiazole in 10 ml of THF is
added dropwise. The reaction mixture is heated to 50.degree. C. and
stirred overnight, cooled and concentrated using a rotary
evaporator. The residue is dissolved in water and adjusted to pH=3
using HCl. A brown solid precipitates out, and this solid is
filtered off and dried under reduced pressure.
[0454] Yield: 714 mg (87.0% of theory).
[0455] M.p.: 210.degree. C. (decomp.)
Example 20A
[0456] Ethyl 5-amino-1-(2-fluorobenzyl)-1H-pyrazole-3-carboxylate
57
[0457] Under argon, 100 g (0.613 mol) of the sodium salt of ethyl
cyanopyruvate (preparation analogously to Borsche and Manteuffel,
Liebigs Ann. 1934, 512, 97) in 2.5 l of dioxane are admixed, with
efficient stirring and at room temperature, with 111.75 g (75 ml,
0.98 mol) of trifluoroacetic acid, and the mixture is stirred for
10 min, during which a large proportion of the starting material
dissolves. 85.93 g (0.613 mol) of 2-fluorobenzylhydrazine are then
added, and the mixture is boiled overnight. After cooling, the
precipitated sodium trifluoroacetate crystals are filtered off with
suction and washed with dioxane, and the crude solution is reacted
further.
Example 21A
[0458] Ethyl
1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylate 58
[0459] The above solution from Example 20A is admixed with 61.25 ml
(60.77 g, 0.613 mol) of dimethylaminoacrolein and 56.28 ml (83.88
g, 0.736 mol) of trifluoroacetic acid, and the mixture is boiled
under argon for 3 days. The solvent is subsequently evaporated
under reduced pressure and the residue is added to 2 l of water,
and the mixture is extracted three times with 1 l of ethyl acetate
in each case. The combined organic phases are dried with magnesium
sulphate and concentrated using a rotary evaporator. The mixture is
chromatographed over 2.5 kg of silica gel and eluted using a
toluene/toluene-ethyl acetate=4:1 gradient.
[0460] Yield: 91.6 g (49.9% of theory over two steps).
[0461] M.p. 85.degree. C.
[0462] Rf (SiO.sub.2, T1E1): 0.83
Example 22A
[0463] 1-(2-Fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide
59
[0464] 10.18 g (34 mmol) of the ester from Example 21A are
initially charged in 150 ml methanol which has been saturated with
ammonia at 0-10.degree. C. The mixture is stirred at room
temperature for two days and subsequently concentrated under
reduced pressure.
[0465] Rf (SiO.sub.2, T1E1): 0.33
Example 23A
[0466] 3-Cyano-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine 60
[0467] 36.1 g (133 mmol) of
1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-- 3-carboxamide from
Example 22A are dissolved in 330 ml of THF and mixed with 27 g (341
mmol) of pyridine. Over a period of 10 min, 47.76 ml (71.66 g, 341
mmol) of trifluoroacetic anhydride are subsequently added, and the
temperature increases to 40.degree. C. during the addition. The
mixture is stirred at room temperature overnight. The mixture is
subsequently poured into 1 l of water, and the mixture is extracted
three times with 0.5 l of ethyl acetate each time. The organic
phase is washed with saturated sodium bicarbonate solution and with
1 N HCl, dried with MgSO.sub.4 and concentrated using a rotary
evaporator.
[0468] Yield: 33.7 g (100% of theory)
[0469] M.p.: 81.degree. C.
[0470] Rf (SiO.sub.2, T1E1): 0.74
Example 24A
[0471] Methyl
1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidat- e
61
[0472] 30.37 g (562 mmol) of sodium methoxide are dissolved in 1.5
l of methanol, and 36.45 g (144.5 mmol) of
3-cyano-1-(2-fluorobenzyl)-1H-pyraz- olo[3,4-b]pyridine from
Example 23A are added. The mixture is stirred at room temperature
for 2 hours and the resulting solution is directly employed in the
next step.
Example
[0473]
1-(2-Fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamidine
62
[0474] The above solution of methyl
(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyr- idine-3-carboximidate from
Example 24A in methanol is admixed with 33.76 g (32.19 ml, 562
mmol) of glacial acetic acid and 9.28 g (173 mmol) of ammonium
chloride, and the mixture is stirred under reflux overnight. The
solvent is evaporated off under reduced pressure, the residue is
triturated well with acetone and the precipitated solid is filtered
off with suction. The product is added to 2 l of water, the mixture
is admixed with stirring with 31.8 g of sodium carbonate and
extracted three times with a total of 1 l of ethyl acetate, and the
organic phase is dried with magnesium sulphate and concentrated
under reduced pressure.
[0475] Yield: 27.5 g (76.4% of theory over two steps)
[0476] M.p.: 86.degree. C.
[0477] Rf (SiO.sub.2, T1EtOH1): 0.08
PREPARATION EXAMPLES
Example 1
[0478]
3-(4-Amino-5-methylsulphonylpyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-p-
yrazolo[3,4-b]pyridine 63
[0479] 2 g (7.42 mmol) of
1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-- carboxamidine
from Example 25A, 1.39 g (7 mmol) of 3-(dimethylamino)-2-(me-
thylsulphonyl)-2-acrylonitrile (which can be prepared analogously
to Example 1A), 0.79 ml (7 mmol) of piperidine and 200 ml of
isoamyl alcohol are stirred at 110.degree. C. for 12 h. After
cooling, the precipitated crystals are filtered off with suction
and washed with diethyl ether. This gives 0.94 g (31.8% of theory)
of the title compound.
[0480] M.p.: 272.degree. C.
[0481] Rf (SiO.sub.2, EE): 0.72
[0482] The following compounds were prepared analogously:
10 64 Ex. No. R M.p. [.degree. C.] Rf (SiO.sub.2) Yield 2
CH.sub.3CH.sub.2CH.sub.2SO.sub.2-- 254 0.87 (EA) 30 3
(CH.sub.3).sub.2CHSO.sub.2-- 268 0.83 (EA) 31.6 4
(CH.sub.3).sub.3C--SO.sub.2-- >280 0.24 (T1E1) 25.4 5
[(CH.sub.3).sub.2CHO].sub.2PO-- 190 0.19 (T1E1) 10.8 6 --CONH.sub.2
215 0.25 (T1E1) 9.6 7 --SO.sub.2-(2-thienyl) 275 0.48 (T1E1) 11.5 8
--CH.sub.2CF.sub.3 181 14.4 9 PhSO.sub.2-- 279 0.51 (T1E1) 29.2 10
PhSO-- 218 0.26 (T1E1) 19.4 11 --(CH.sub.2).sub.5CN 107 0.22 (EA)
18 12 --(CH.sub.2).sub.7CN 147 0.36 (EA) 13.5 13
--CH.sub.2CH.sub.2--CN 201 0.2 (T4EtOH1) 12
[0483] The corresponding 3-dimethylaminoacrylonitriles where the
respective substituent R is in the 2-position, which are to be
reacted, as starting materials of Examples 2 to 13, with the
amidine 24A, can be prepared analogously to Examples 1A and 3A.
Example 14
[0484]
3-[5-Cyano-4-(4-methylphenyl)pyrimidin-2-yl]-1-(2-fluorobenzyl)-1H--
pyrazolo[3,4-b]pyridine 65
[0485] At 110.degree. C., 200 mg (0.74 mmol) of
1-(2-fluorobenzyl)-1H-pyra- zolo[3,4-b]pyridine-3-carboxamidine
from Example 25A, 171 mg (0.8 mmol) of
(dimethylamino)-2-(4-methylbenzoyl)-2-acrylonitrile (which can be
prepared analogously to Example 1), 0.68 mg (0.8 mmol) of
piperidine and 20 ml of 2-pentanol are stirred for 12 h. After
cooling, the solvent is evaporated under reduced pressure and the
residue is chromatographed over silica gel. This gives 217 mg
(69.5% of theory) of the title compound.
[0486] M.p.: 229.degree. C.
Example 15
[0487]
3-(4,6-Diamino-5-benzylpyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-pyrazo-
lo[3,4-b]pyridine 66
[0488] At 110.degree. C., 200 mg (0.74 mmol) of
1-(2-fluorobenzyl)-1H-pyra- zolo[3,4-b]pyridine-3-carboxamidine
from Example 25A, 125 mg (0.8 mmol) of 2-benzylmalonodinitrile
(preparable from malonodinitrile and benzyl bromide using a base
such as potassium carbonate), 0.68 mg (0.8 mmol) of piperidine and
20 ml of 2-pentanol are stirred for 12 h. After cooling, the
solvent is evaporated under reduced pressure and the residue is
chromatographed over silica gel. This gives 165 mg (52.2% of
theory) of the title compound.
[0489] M.p.: 193.degree. C.
Example 16
[0490]
3-(4,6-Diamino-5-N-morpholinopyrimidin-2-yl)-1-(2-fluorobenzyl)-1H--
pyrazolo[3,4-b]-pyridine 67
[0491] At 105.degree. C., 200 mg (0.74 mmol) of
1-(2-fluorobenzyl)1H-pyraz- olo[3,4-b]pyridine-3-carboxamidine from
Example 25A and 400 mg (2.65 mmol) of 2-N-morpholinomalonodinitrile
(for the synthesis cf. H. Gold and O. Bayer, Chem. Ber. 1961, 94,
2594) are heated under reduced pressure for 12 h. The solid residue
is dissolved in DMF, silica gel is added and the solvent is
evaporated under reduced pressure. Chromatography gives 222 mg
(71.1% of theory) of the title compound.
[0492] M.p.: 261.degree. C.
[0493] Rf: (EA): 0.2
[0494] The following compounds were prepared analogously:
11 68 Ex. No. R Yield Rf (SiO.sub.2) 17 (from 25A and diethyl
2-(1H-1,2,4- triazolyl)-malonate (preparable analogously to Example
7A)) 69 29.5 0.32 (BABA) 18 (from 25A and 10A) 70 11.9 0.36 (BABA)
19 (from 25A and ethyl 2-acetamidocyano- acetate (commercially
available)) 71 12.9 0.61 (BABA) 20 (from 25A and diethyl
2-N-pyrrolomalonate (commercially available)) 72 15.2 0.63 (EA)
Yield (% of Ex. No. R theory) Rf (SiO.sub.2) 21 (From 25A and 8A)
73 82.7 0.07 (BABA) 22 (from 25A and hydroxyimino- malonitrile,
sodium salt (commercially available)) 74 1.8 0.50 (EA) 23 (from 25A
and 12A) 75 43.3 0.85 (BABA) 24 (from 25A and 13A) 76 72.4 0.72
(BABA) 25 (from 25A and 2-N- dimethylaminomalo- nodinitrile (for
the synthesis, cf. Chem. Ber. 1961, 94, 2594)) 77 41.6 0.52 (BABA)
26 (from 25A and 2-N- diethylaminomalono- dinitrile (for the
synthesis, cf. Chem. Ber. 1961, 94, 2594)) 78 58.4 0.75 (BABA) 27
(from 25A and 14A) 79 52.3 0.27 (BABA) 28 (from 25A and 9A) 80 54.8
0.65 (BABA) 29 (from 25A and 15A) 81 55.1 0.48 (BABA) 30 (from 25A
and 16A) 82 crude 0.08 (BABA) 31 (from 25A and 17A) 83 35.3 0.50
(EA) 32 (from 25A and 18A) 84 97.7 0.53 (BABA) 33 (from 25A and
2-(thiazol-2-yl)- malonodinitrile (Synthese: Hetero- cycles, 1990,
31, 1115) 85 22.1 0.85 (BABA) 34 (from 25A and 19A) 86 1.2 0.63
(BABA) 35 (from 25A and 2-methylsulphonyl- malonodinitrile) 87 11.3
0.90 (BABA)
Example 36
[0495]
3-(4,6-Bis(trifluoromethyl)-pyrimidin-2-yl)-1-(2-fluorobenzyl)1H-py-
razolo[3,4-b]pyridine 88
[0496] At 110.degree. C., 50 mg (19 mmol) of
1-(2-fluorobenzyl)-1H-pyrazol- o[3,4-b]pyridine-3-carboxamidine
from Example 25A and 42 mg (20 mmol) of
1,1,1,5,5,5-hexafluoroacetylacetone are heated for 5 h.
Chromatography gives 33 mg (40.3% of theory) of the title
compound.
[0497] M.p.: 109.degree. C.
[0498] Rf: (toluene): 0.35
Example 37
[0499]
3-(5-Ethoxycarbonyl-4-trifluoromethyl-pyrimidin-2-yl)-1-(2-fluorobe-
nzyl)-1H-pyrazolo[3,4-b]pyridine 89
[0500] 600 mg of the crude
1-(2-fluorobenzyl)1H-pyrazolo[3,4-b]pyridine-3-- carboxamidine
hydrochloride (preparable from the amidine 25A by reaction with
HCl) are stirred in 30 ml of methanol with 106 mg of sodium
methoxide and admixed with 472 mg (1.96 mmol) of ethyl
3-ethoxy-2-trifluoroacetyl-acrylate. The mixture is boiled for 12
hours and the precipitate is then filtered off with suction and
washed with ether. This gives 249 mg (27.5% of theory) of
crystals.
[0501] M.p.: 174.degree. C.
[0502] Rf: SiO.sub.2 T1E1: 0.76
Example 38
[0503] Diethyl
4-amino-2-{1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-y-
l}-pyrimidine-5-phosphonate 90
[0504] 2.44 g (9.00 mmol) of the amidine from Example 25A and 3.71
g (16.0 mmol) of diethyl
1-cyano-1-(dimethylamino)methylene-methanephosphonate (Aboujaoude,
Elie Elia; Collignon, Noel; Savignac, Philippe, Tetrahedron, 41,
1985, 427-434) were mixed well, treated for 5 minutes with
ultrasound and subsequently stirred at 100.degree. C. under reduced
pressure (membrane pump) overnight. The mixture was cooled to room
temperature, stirred with hot methanol and freed from insoluble
components by filtration. The filtrate was concentrated and
chromatographed over silica gel (CC:E 1:1E).
[0505] Yield: 638 mg (16%)
[0506] M.p.: 185.degree. C.
[0507] R.sub.f-value: 0.09 (C:E 1:1)
Example 39
[0508]
3-(4-amino-5-N-morpholino-pyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-pyr-
azolo[3,4-b]pyridine 91
[0509] 1.00 g (3.72 mmol) of the amidine from Example 25A and 2.00
g (11.0 mmol) of 3-(dimethylamino)-2-morpholino-acrylonitrile from
Example 3A were mixed well, treated with ultrasound for 5 minutes
and subsequently stirred at 120.degree. C. under reduced pressure
(membrane pump) overnight. The mixture was cooled to room
temperature and stirred with tert-butyl methyl ether, and the
resulting precipitate was filtered off with suction and
chromatographed over silica gel (C:E 100:1C:E 1:1).
[0510] Yield: 262 mg (17%)
[0511] M.p.: 205.degree. C.
[0512] R.sub.f-value: 0.05 (C:E 1:1)
Example 40
[0513]
3-(4-Amino-5-N-thiomorpholino-pyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-
-pyrazolo[3,4-b]pyridine 92
[0514] 5.00 g (18.6 mmol) of the amidine from Example 25A and 9.98
g (50.7 mmol) of 3-(dimethylamino)-2-thiomorpholinoacrylonitrile
from 4A were mixed well, treated with ultrasound for 5 minutes and
subsequently stirred at 100.degree. C. under reduced pressure
(membrane pump) overnight. The mixture was cooled to room
temperature and stirred with tert-butyl methyl ether, and the
resulting precipitate was filtered off with suction.
[0515] Yield: 1.43 g (18%)
[0516] M.p.:>250.degree. C.
[0517] R.sub.f-value: 0.06 (C:EE 1:1)
Example 41
[0518]
3-(4-Hydroxy-5-(methylsulphonyl)-pyrimidin-2-yl)-1-(2-fluorobenzyl)-
-1H-pyrazolo[3 ,4-b]pyridine 93
[0519] 2.32 g (8.61 mmol) of the amidine from Example 25A and 5.71
g (25.8 mmol) of the enamine from Example 5A are admixed and heated
in an open vessel at 100-105.degree. C. for 4 hours. The residue is
cooled, digested with toluene and filtered, and the filtrate is
washed with toluene.
[0520] Yield: 1.16 g (33.6% of theory).
[0521] Rf (SiO.sub.2, EA): 0.23
Example 42
[0522]
3-(6-Chloro-8-methyl-9H-purin-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo[-
3,4-b]pyridine 94
[0523] 650 mg (1.65 mmol) of the hydroxypyrimidine from Example 19
are taken up in 3 ml of phosphorus oxytrichloride, two drops of
N,N-dimethylaniline are added, and the solution is heated at reflux
for three hours. The reaction mixture is cooled and concentrated
using a rotary evaporator. The residue is taken up in ethyl
acetate, washed carefully with saturated sodium bicarbonate
solution, dried and concentrated using a rotary evaporator. The
crude product is reacted further.
[0524] Yield: 580 mg (89.1% of theory).
[0525] Rf (SiO.sub.2, EA): 0.21
[0526] The following compounds were prepared analogously to the
preparation of Example 42:
12 95 Yield (% of Ex No. Starting material Product theory) Rf
(SiO.sub.2) 43 96 97 59.6 0.70 (EA) 44 98 99 not determined (crude
product) 0.65 (C1E1) 45 100 101 21.4 0.45 (C1E2)
[0527] The starting material from Example 43 was prepared as
Example 17. The starting material from Example 44 was prepared as
Example 20. The starting material from Example 45 was prepared as
Example 41.
Example 46
[0528]
3-(5-Ethyl-4-(2-hydroxyethylaminocarbonyl)pyrimidin-2-yl)-1-(2-fluo-
robenzyl)-1H-pyrazolo[3,4-b]pyridine 102
[0529] 70.0 mg (0.179 mmol) of the methylester (prepared from 25A
and methyl 4-(dimethylamino)-3-ethyl-2-oxo-3-butenoate analogously
to Example 36) are dissolved in 109.3 mg (1.78 mmol) of the amine,
and the mixture is stirred at 60.degree. C. for 3 hours.
Dichloromethane is added, and the mixture is washed once with a
0.5N hydrochloric acid solution. The organic phase is dried with
magnesium sulphate and concentrated under reduced pressure. Yield:
30.6 mg (40.7% of theory)
[0530] Rf (SiO.sub.2, E) 0.31
[0531] The following compounds were prepared in an analogous manner
by reaction with the appropriate amines:
13 103 Ex. No. R Yield Rf (SiO.sub.2) 47 104 36.0 0.48 (C1E2) 48
105 13.2 0.20 (C1E2) 49 106 crude 0.12 (C1E2) 50 107 22.0 0.37
(C1E2) 51 108 crude 0.42 (E) 52 109 22.8 0.05 (C1E2) 53 110 crude
0.37 (C1E2) 54 111 crude 0.61 (C1E2) 55 112 87.0 0.65 (C1E2) 56 113
57.7 0.66 (C1E2) 57 --NH.sub.2 86.9 0.26 (C1E2)
[0532] The amines which are to be used as starting materials are in
each case commercially available or obtainable in a simple manner
by standard methods known to the person skilled in the art, such as
those described, for example, in J. March, Advanced Organic
Chemistry, 3rd ed., Wiley, 1985, p. 1153 f.
Example 58
[0533]
3-(4-(4,5-Dihydro-1H-imidazol-2-yl)-5-ethyl-pyrimidin-2-yl)-1-(2-fl-
uorobenzyl)-1H-pyrazolo[3,4-b]pyridine 114
[0534] 68.9 mg (1.15 mmol) of ethylenediamine are dissolved in 10
ml of toluene, 0.60 ml (1.15 mmol) of a 2M solution of
trimethylaluminium and toluene are added at 0.degree. C., and the
mixture is stirred at room temperature for 2 hours. 155 mg (0.38
mmol) of the ethyl ester (prepared from 25A and ethyl
4-(dimethylamino)-3-ethyl-2-oxo-3-buteneoate analogously to Example
36) are then added. The mixture is stirred at 75.degree. C. for
five days, cooled and washed once with sodium potassium tartrate
solution, and the aqueous phase is extracted once with
dichloromethane. The combined organic phases are dried with
magnesium sulphate, admixed with 500 mg of silica gel and
concentrated using a rotary evaporator.
[0535] For purification, the substance is chromatographed over 10 g
of silica gel 60 (particle size 0.040-0.063 mm) using ethyl acetate
to ethyl acetate/methanol 9:1 as mobile phase. Yield 75.0 mg (49%
of theory).
[0536] Rf (SiO.sub.2, C1E1): 0.04
Example 59
[0537]
3-[5-ethyl-4-(1H-imidazol-2-yl)-pyrimidin-2-yl]-1-(2-fluorobenzyl)--
1H-pyrazolo[3,4-b]pyridine 115
[0538] 62 mg (0.15 mmol) of the dihydroimidazole from Example 58
and 100 mg of palladium/carbon (10%) are heated to reflux in 5 ml
of toluene. After 6 days, the mixture is filtered off and the
solvent is evaporated under reduced pressure.
[0539] For purification, the substance is chromatographed over 8 g
of silica gel 60 (particle size 0.040-0.063 mm) using
cyclohexane/ethyl acetate 2:1 to 1:2 as mobile phase.
[0540] Yield: 8.8 mg (14.3% of theory)
[0541] Rf (SiO.sub.2, C1E2): 0.24
Example 60
[0542]
3-(5-Ethyl-4-(1H-imidazol-1-yl)-pyrimidin-2-yl)-1-(2-fluorobenzyl)--
1H-pyrazolo[3,4-b]pyridine 116
[0543] 60 mg (0.16 mmol) of the chloro compound (prepared from 25A
and ethyl 2-formylbutanoate analogously to Example 36 and
subsequent reaction with phosphorus oxytrichloride analogously to
Example 42) and 22.2 mg (0.33 mmol) of imidazole are dissolved in 5
ml of dimethylformamide and admixed with 33.8 mg (0.24 mmol) of
potassium carbonate. The mixture is stirred at 100.degree. C.
overnight. The mixture is cooled, diluted with ethyl acetate and
washed twice with water. The organic phase is dried using magnesium
sulphate and concentrated under reduced pressure. Yield: 47.4 mg
(72.7% of theory).
[0544] Analogously to Example 60, the following compounds were
prepared by reaction with the appropriate amines:
14 117 Ex. No. R.sup.1 R.sup.2 Yield Rf (SiO.sub.2) 61 (from 45)
SO.sub.2CH.sub.3 118 79.3 0.58 (E) 62 (from 45) SO.sub.2CH.sub.3
119 58.3 0.34 (C1E2) 63 (from 45) SO.sub.2CH.sub.3 120 29.0 0.43
(C1E2) 64 (see Ex. 60) CH.sub.2CH.sub.3 121 25.6 0.18 (C1E2) 65
(see Ex. 60) CH.sub.2CH.sub.3 122 11.4 0.11 (C1E2) 66 (see Ex. 60)
CH.sub.2CH.sub.3 123 crude 0.36 (C1E2) 67 (see Ex. 60)
CH.sub.2CH.sub.3 124 crude 0.22 (C1E2) 68 (see Ex. 60)
CH.sub.2CH.sub.3 125 crude 0.14 (C1E2) 69 (see Ex. 60)
CH.sub.2CH.sub.3 126 7.7 0.03 (C1E2) 70 (see Ex. 60)
CH.sub.2CH.sub.3 127 8.8 0.30 (C1E2)
Examples 71-79
[0545] The chlorine group of the compounds of Examples 42 to 45 can
be reduced by known methods using ammonium formate and
palladium/carbon, or be exchanged by reaction with nucleophiles
such as the azide anion, ammonia, amines or methanol. The azide
group introduced in this manner can in turn be reduced with sodium
dithionite. In this manner, the following compounds are
obtained:
15 128 Yield (% of Ex. No. R theory) Rf (SiO.sub.2) 71 (from 42)
129 53.7 0.25 (EA) 72 (from 42) 130 26.8 0.69 (BABA) 73 (from 42)
131 13.8 0.61 (BABA) 74 (from 42) 132 crude 0.78 (BABA) 75 (from
44) 133 crude 0.53 (BABA) 76 (from 44) 134 crude 0.77 (EA) 77 (from
43) 135 9.8 78 (from 43) 136 10.6 0.73 (BABA) 79 (from 43) 137 18.9
0.29 (EA)
Example 80
[0546]
3-(4-Diacetylamino-5-ethyl-pyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-py-
razolo[3,4-b]pyridine 138
[0547] 50.0 mg (0.14 mmol) of the amine (preparable analogously to
Example 60 by reaction of the chloro compound described therein
with ammonia or with sodium azide and subsequent reduction with
sodium dithionide) are dissolved in dichloromethane and admixed
with 33.8 mg (0.43 mmol) of acetyl chloride and 68.1 mg (0.86 mmol)
of pyridine. The solution is stirred at RT for 4 hours, washed once
with 1N HCl and then with saturated NaHCO.sub.3 solution. The
organic phase is dried using magnesium sulphate and concentrated
under reduced pressure. For purification, the substance was
chromatographed over silica gel 60 (particle size 0.040-0.063 mm)
using cyclohexane/ethyl acetate 1:1 as mobile phase. Yield: 33.2 mg
(53.5% of theory)
[0548] Rf (SiO.sub.2, C1E2): 0.41
Example 81
[0549]
3-[4-(2-Benzoyloxymethylbenzoylamino)-5-ethylpyrimidin-2-yl]-1-(2-f-
luorobenzyl-1H-pyrazolo[3,4-b]pyridine 139
[0550] At room temperature, 9 mg (0.23 mmol) of sodium hydride (60%
strength suspension in oil) are suspended in 1 ml of
tetrahydrofuran (THF). A solution of 40 mg (0.11 mmol) of the amine
(cf. Example 80) in 0.8 ml of THF is added, and a solution of 34.7
mg (0.13 mmol) of 2-(benzoyloxymethyl)benzoyl chloride is then
added. After 30 min, another 5 ml (0.12 mmol) of sodium hydride
(60% strength) and 14 mg (0.05 mmol) of the abovementioned acyl
chloride are added. After 1 h, the mixture is admixed with water
and extracted with ethyl acetate, and the organic phase is washed
with 1M hydrochloric acid and saturated NaHCO.sub.3 solution, dried
with magnesium sulphate and concentrated under reduced pressure.
The substance is recrystallized from cyclohexane/ethyl acetate.
[0551] Yield: 25 mg (37.1% of theory)
[0552] Rf (SiO.sub.2, C1E1): 0.50
Example 82
[0553]
3-(4-Acetoxy-5-ethyl-pyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo-
[3,4-b]pyridine and
3-(3-acetyl-5-ethyl-pyrimidin-4-on-2-yl)-1-(2-fluorobe-
nzyl)-1H-pyrazolo[3,4-b]pyridine 140
[0554] 73.8 mg (0.21 mmol) of the hydroxypyrimidine compound
(prepared from 25A and ethyl 2-formylbutanoate analogously to
Example 36) are dissolved in 2 ml of dichloromethane and admixed
with 27.9 mg (0.27 mmol) of triethylamine and 25.9 mg (0.25 mmol)
of acetic anhydride. The solution is stirred at RT for three hours,
taken up in ethyl acetate and washed once with water, and the
aqueous phase is extracted once with ethyl acetate. The combined
organic phases are washed two more times with water, dried with
magnesium sulphate and concentrated using a rotary evaporator.
Yield: 42.0 mg (50.8% of theory)
[0555] Rf (SiO.sub.2, C1E2): 0.5
Example 83
[0556]
3-(5-Ethyl-4-(methylsulphinyl)-pyrimidin-2-yl)-1-(2-fluorobenzyl)-1-
H-pyrazolo[3,4-b]pyridine and
3-(5-ethyl-4-(methylsulphonyl)pyrimidin-2-yl-
)-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine 141
[0557] 45.2 mg (0.12 mmol) of the methyl thioether (prepared from
the chloro compound used in Example 60 by reaction with sodium
methanethiolate in toluene) and 30.8 mg (0.18 mmol) of MCPBA are
stirred at 0.degree. C. in 2 ml of dichloromethane. After three
hours, the reaction mixture is admixed with sodium bicarbonate
solution and ethyl acetate, separated, dried and concentrated using
a rotary evaporator.
[0558] For purification, the substance is chromatographed over 8 g
of silica gel 60 (particle size 0.040-0.063 mm) using
cyclohexane/ethyl acetate 1:1 to 1:4 as mobile phase.
[0559] B: Yield: 36.0 mg (76.4% of theory). Rf (SiO.sub.2, C1E2):
0.057
[0560] C: Yield: 7.1 mg (14.5% of theory). Rf (SiO.sub.2, C1E2):
0.79
Example 84
[0561]
3-(4,6-Diamino-5-N-4-oxothiomorpholinopyrimidin-2-yl)-1-(2-fluorobe-
nzyl)-1H-pyrazolo[3,4-b]pyridine and
3-(4,6-diamino-5-N-4,4-dioxothiomorph-
olinopyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine
142
[0562] 230 mg (0.53 mmol) of the thiomorpholine from Example 23 and
130 mg (0.53 mmol) of MCPBA are stirred at 0.degree. C. in 5 ml of
dichloromethane. After 30 min, an identical amount of MPCBA is
added. After 1.5 hours, the reaction mixture is mixed with silica
gel and concentrated using a rotary evaporator. For purification,
the substance is chromatographed over silica gel 60 (particle size
0.040-0.063 mm) using cyclohexane/ethyl acetate.
[0563] B: Yield: 86 mg (36.1% of theory). Rf (SiO.sub.2, BABA):
0.18
[0564] C: Yield 14 mg (5.7% of theory). Rf (SiO.sub.2, BABA):
0.41
* * * * *