138
Claims
1. Triazolopurines of general formula (I)
<IMG>
wherein
R1 or R3 denotes hydrogen, an optionally substituted
C1-10-alkyl, C2-10-alkenyl or C2-10-alkynyl, an
optionally substituted C3-8-cycloalkyl, an
optionally substituted C4-8-cycloalkenyl or an
optionally substituted C6-8-cycloalkynyl;
R1 or R3 denotes an optionally substituted C6-10-aryl-C1-6-alkyl,
C6-10-aryl-C2-6-alkenyl, C6-10-aryl-C2-6-alkynyl,
an optionally substituted C6-10-aryl
or an optionally substituted heteroaryl, an
optionally substituted 5-, 6- or 7-membered
heterocyclic group which contains as heteroatoms
one or more atoms from the group comprising
nitrogen, oxygen or sulphur, the heterocycle
being linked via a carbon atom of the ring;
R1 or R3 denotes an optionally substituted
C1-10-alkyloxycarbonyl, an optionally substituted
C2-10-alkenyloxycarbonyl, an optionally
substituted C2-10-alkynyloxycarbonyl, an
optionally substituted C3-8-cycloalkyloxy-carbonyl,
an optionally substituted
C6-10-aryloxycarbonyl, an optionally substituted
C6-10-aryl-C1-6-alkyloxycarbonyl, A-O-CO- wherein A
denotes an optionally substituted 5-, 6- or
7-membered heterocyclic group which contains as
139
heteroatoms one or more atoms selected from the
group comprising nitrogen, oxygen or sulphur,
wherein A is linked via a carbon atom of the
ring,
R1 or R3 is an optionally substituted
C1-10-alkyl-sulphonyl, C2-10-alkenylsulphonyl,
C2-10-alkynylsulphonyl, an optionally substituted
C3-8-cycloalkylsulphonyl, an optionally
substituted C6-10-arylsulphonyl, an optionally
substituted C6-10-aryl-C1-6-alkylsulphonyl, a group
A-SO2- wherein A is as hereinbefore defined and
is linked via a carbon atom of the ring;
R1 or R3 denotes an optionally substituted
C1-10-alkylcarbonyl, an optionally substituted
C2-10-alkenylcarbonyl, an optionally substituted
C2-10-alkynylcarbonyl, an optionally substituted
C3-8-cycloalkylcarbonyl, an optionally
substituted C6-10-arylcarbonyl, an optionally
substituted C6-10-aryl-C1-6-alkylcarbonyl, a group
A-CO- wherein A is as hereinbefore defined;
R1 or R3 denotes a group of general formula
<IMG>
wherein
R denotes hydrogen, phenyl, substituted phenyl, an
optionally substituted benzyl, an optionally
substituted C3-6-cycloalkyl group, a branched or
unbranched C1-10-alkyl, preferably C1-4-alkyl,
C2-10-alkenyl or C2-10-alkynyl group which may
optionally be substituted by hydroxy, phenyl,
substituted phenyl, amino or substituted amino;
140
R2 denotes hydrogen, hydroxy, amino, halogen,
nitro, CF3, COOH, mercapto, C1-6-alkylmercapto,
an optionally substituted C1-10-alkyl, an
optionally substituted C2-10-alkenyl, an
optionally substituted C2-10-alkynyl, an
optionally substituted C3-8-cycloalkyl, an
optionally substituted C5-8-cycloalkanone, an
optionally substituted C4-8-cycloalkenyl, an
optionally substituted C6-8-cycloalkynyl, an
optionally substituted C6-10-aryl, an optionally
substituted C6-10-aryl-C1-6-alkyl, C6-10-aryl-
C2-6-alkenyl, C6-10-aryl-C2-6-alkynyl,
C3-8-cycloalkyl-C1-6-alkyl, C3-8-cycloalkyl-
C2-6-alkenyl, or C3-8-cycloalkyl-C2-6-alkynyl;
R2 denotes an optionally substituted 5-, 6- or
7-membered heterocyclic group which contains as
heteroatom one or more atoms selected from the
group comprising nitrogen, oxygen or sulphur,
wherein the nitrogen may optionally be
substituted and the heterocyclic group may be
linked via a carbon or nitrogen atom directly or
via a C1-6-alkyl, C2-6-alkenyl or C2-6-alkynyl
bridge;
R2 denotes an optionally substituted
C1-10-alkylsulphonyl, C2-10-alkenylsulphonyl or
C2-10-alkynylsulphonyl, an optionally substituted
C3-8-cycloalkylsulphonyl, an optionally
substituted C6-10-arylsulphonyl, an optionally
substituted heteroarylsulphonyl or an optionally
substituted C6-10-aryl-C1-6-alkylsulphonyl;
R2 denotes an optionally substituted
C1-10-alkylsulphonyloxy, C2-10-alkenylsulphonyloxy
or C2-10-alkynylsulphonyloxy, an optionally
substituted C3-8-cycloalkylsulphonyloxy, an
optionally substituted C6-10-arylsulphonyloxy, an
141
optionally substituted C6-10-aryl-C1-6-
alkylsulphonyloxy or an optionally substituted
heteroarylsulphonyloxy;
R2 denotes an optionally substituted
C1-10-alkylsulphonylamino, C2-10-alkenylsulphonylamino
or C2-10-alkynylsulphonylamino, an
optionally substituted C3-8-cycloalkyl-
sulphonylamino, an optionally substituted
C6-10-arylsulphonylamino, an optionally
substituted C6-10-aryl-C1-6-alkylsulphonylamino, or
an optionally substituted heteroarylsulphonylamino;
R2 denotes an optionally substituted
C1-10-alkylaminocarbonyl, C1-10-dialkylaminocarbonyl,
C1-10-alkyl-C2-10-alkenylaminocarbonyl,
C2-10-alkenylaminocarbonyl, C2-10-dialkenylaminocarbonyl,
C2-10-alkynylaminocarbonyl or
C1-10-alkyl-C2-10-alkynylaminocarbonyl, an
optionally substituted C3-8-cycloalkyl-
aminocarbonyl, an optionally substituted
C6-10-arylaminocarbonyl, an optionally
substituted C6-10-aryl-C1-6-alkylaminocarbonyl, or
an optionally substituted heteroarylaminocarbonyl;
R2 denotes an optionally substituted
C1-10-alkyloxycarbonylamino, C2-10-alkenyloxy-
carbonylamino or C2-10-alkynyloxycarbonylamino,
an optionally substituted C3-8-cycloalkyloxy-
carbonylamino, an optionally substituted
C6-10-aryloxycarbonylamino, an optionally
substituted C6-10-aryl-C1-6-alkyloxycarbonylamino
or an optionally substituted heteroaryloxy-
carbonylamino;
142
R2 denotes an optionally substituted
C1-10-alkylaminocarbonyloxy, C2-10-alkenylamino-
carbonyloxy or C2-10-alkynylaminocarbonyloxy, an
optionally substituted C3-8-cycloalkylamino-
carbonyloxy, an optionally substituted
C6-10-arylaminocarbonyloxy, an optionally
substituted C6-10-aryl-C1-6-alkylaminocarbonyloxy
or an optionally substituted heteroarylamino-
carbonyloxy;
R2 denotes an optionally substituted C1-10-alkyl-N-amidino,
C2-10-alkenyl-N-amidino or C2-10-alkynyl-N-amidino,
an optionally substituted
C3-8-cycloalkyl-N-amidino, an optionally
substituted C6-10-aryl-N-amidino, an optionally
substituted C6-10-aryl-C1-6-alkyl-N-amidino or an
optionally substituted heteroaryl-N-amidino;
R2 denotes an optionally substituted C1-10-alkyloxy,
C2-10-alkenyloxy or C2-10-alkynyloxy, an optionally
substituted C3-8-cycloalkyloxy, an optionally
substituted C6-10-aryloxy, an optionally
substituted C6-10-aryl-C1-6-alkyloxy or an
optionally substituted heteroaryloxy;
R2 denotes an optionally substituted
C1-10-alkyloxycarbonyl, C2-10-alkenyloxycarbonyl or
C2-10-alkynyloxycarbonyl, an optionally
substituted C3-8-cycloalkyloxycarbonyl, an
optionally substituted C6-10-aryloxycarbonyl, an
optionally substituted C6-10-aryl-C1-6-alkyloxy-carbonyl
or an optionally substituted
heteroaryloxycarbonyl;
R2 denotes an optionally substituted
C1-10-alkylcarbonyloxy, C2-10-alkenylcarbonyloxy or
C2-10-alkynylcarbonyloxy, an optionally
substituted C3-8-cycloalkylcarbonyloxy, an
143
optionally substituted C6-10-arylcarbonyloxy, an
optionally substituted C6-10-aryl-C1-6-alkyl-
carbonyloxy or an optionally substituted
heteroarylcarbonyloxy;
R2 denotes an optionally substituted
C1-10-alkylthio, C2-10-alkenylthio or
C2-10-alkynylthio, an optionally substituted
C3-8-cycloalkylthio, an optionally substituted
C6-10-arylthio, an optionally substituted
C6-10-aryl-C1-6-alkylthio or an optionally
substituted heteroarylthio;
R2 denotes an optionally substituted amine,
preferably NR8R9;
R2 denotes an optionally substituted group of the
formula
<IMG> <IMG> <IMG>
R2 denotes an optionally substituted group of the
formula
<IMG> <IMG> <IMG>
<IMG> <IMG>
144
wherein Y is a single bond or an alkylene, an
alkenylene or an alkynylene having up to 6,
preferably up to 4 carbon atoms in the chain;
R2 denotes an optionally substituted group of the
formula
<IMG> <IMG>
<IMG> <IMG>
wherein Y is a single bond or an alkylene, an
alkenylene or an alkynylene having up to 6,
preferably up to 4 carbon atoms in the chain;
R4 or R5 denotes a hydrogen atom, an optionally
substituted C1-10-alkyl, C2-10-alkenyl or
C2-10-alkynyl, an optionally substituted
C3-8-cycloalkyl, an optionally substituted
C4-8-cycloalkenyl or an optionally substituted
C6-8-cycloalkynyl, an optionally substituted
C6-10-aryl-C1-6-alkyl, C6-10-aryl-C2-6-alkenyl,
C6-10-aryl-C2-6-alkynyl, an optionally substituted
C6-10-aryl or an optionally substituted
heteroaryl;
R4 or R5 denotes an optionally substituted 5-, 6- or
7-membered heterocyclic group which contains as
heteroatoms one of more atoms selected from the
group comprising nitrogen, oxygen or sulphur,
the heterocyclic group being bound via a carbon
atom of the ring;
145
R4 or R5 denotes an optionally substituted
C1-10-alkyloxycarbonyl, an optionally substituted
C2-10-alkenyloxycarbonyl, an optionally
substituted C2-10-alkynyloxycarbonyl, an
optionally substituted C3-8-cycloalkyloxycarbonyl,
an optionally substituted C6-10-aryl-
C16-alkyloxycarbonyl, an optionally substituted
C6-10-aryloxycarbonyl;
R4 or R5 denotes A-O-CO- wherein A denotes an optionally
substituted 5-, 6- or 7-membered heterocyclic
group which contains as heteroatoms one or more
atoms selected from the group comprising
nitrogen, oxygen or sulphur;
R4 or R5 denotes an optionally substituted
C1-10-alkylsulphonyl, C2-10-alkenylsulphonyl,
C2-10-alkynylsulphonyl, an optionally substituted
C3-8-cycloalkylsulphonyl, an optionally
substituted C6-10-arylsulphonyl, a group
A-SO2- wherein A is as hereinbefore defined and is
linked via a carbon atom of the ring;
R4 or R5 denotes an optionally substituted
C1-10-alkylcarbonyl, an optionally substituted
C2-10-alkenylcarbonyl, an optionally substituted
C2-10-alkynylcarbonyl, an optionally substituted
C3-8-cycloalkylcarbonyl, an optionally
substituted C6-10-arylcarbonyl, an optionally
substituted C6-10-aryl-C1-6-alkylcarbonyl, a group
A-CO- wherein A is as hereinbefore defined;
R4 or R5 denotes a group of general formula
<IMG>
146
wherein
R denotes hydrogen, phenyl, substituted phenyl, an
optionally substituted benzyl, an optionally
substituted C3-6-cycloalkyl group, a branched or
unbranched C1-10-alkyl, preferably C1-4-alkyl,
C2-10-alkenyl or C2-10-alkynyl group, which may
optionally be substituted by hydroxy, phenyl,
substituted phenyl, amino or substituted amino;
R6 denotes hydrogen, hydroxy, -CHO, amino, halogen,
nitro, CF3, COOH, mercapto, C1-6-alkylmercapto,
an optionally substituted C1-10-alkyl, an
optionally substituted C2-10-alkenyl, an
optionally substituted C2-10-alkynyl, an
optionally substituted C3-8-cycloalkyl, an
optionally substituted C5-8-cycloalkanone, an
optionally substituted C4-8-cycloalkenyl, an
optionally substituted C6-8-cycloalkynyl, an
optionally substituted C6-10-aryl, an optionally
substituted C6-10-aryl-C1-6-alkyl, C6-10-aryl-
C2-6-alkenyl, C6-10-aryl-C2-6-alkynyl, an optionally
substituted C3-8-cycloalkyl-C1-6-alkyl,
C3-8-cycloalkyl-C2-6-alkenyl or C3-8-cycloalkyl-
C2-6-alkynyl;
R6 denotes an optionally substituted 5-, 6- or
7-membered heterocyclic group which contains as
heteroatom one or more atoms selected from the
group comprising nitrogen, oxygen or sulphur,
wherein the nitrogen may optionally be
substituted and the heterocyclic group may be
linked via a carbon atom or nitrogen atom
directly or via a C1-6-alkyl, C2-6-alkenyl or
C2-6-alkynyl bridge;
R6 denotes an optionally substituted
C1-10-alkylsulphonyl, C2-10-alkenylsulphonyl or
C2-10-alkynylsulphonyl, an optionally substituted
147
C3-8-cycloalkylsulphonyl, an optionally
substituted C6-10-arylsulphonyl, an optionally
substituted C6-10-aryl-C1-6-alkylsulphonyl or an
optionally substituted heteroarylsulphonyl;
R6 denotes an optionally substituted
C1-10-alkylsulphonyloxy, C2-10-alkenylsulphonyloxy
or C2-10-alkynylsulphonyloxy, an optionally
substituted C3-8-cycloalkylsulphonyloxy, an
optionally substituted C6-10-arylsulphonyloxy, an
optionally substituted C6-10-aryl-C1-6-alkyl-
sulphonyloxy or an optionally substituted
heteroarylsulphonyloxy;
R6 denotes an optionally substituted
C1-10-alkylsulphonylamino, C2-10-alkenylsulphonyl-
amino or C2-10-alkynylsulphonylamino, an
optionally substituted C3-8-cycloalkylsulphonyl-
amino, an optionally substituted
C6-10-arylsulphonylamino, an optionally
substituted C6-10-aryl-C1-6-alkylsulphonylamino or
an optionally substituted heteroarylsulphonyl-
amino;
R6 denotes an optionally substituted C1-10-alkyl-
aminocarbonyl, C1-10-dialkylaminocarbonyl,
C1-10-alkyl-C2-10-alkenylaminocarbonyl,
C2-10-alkenylaminocarbonyl, C2-10-dialkenylamino-
carbonyl, C2-10-alkynylaminocarbonyl or
C1-10-alkyl-C2-10-alkynylaminocarbonyl, an
optionally substituted C3-8-cycloalkylamino-
carbonyl, an optionally substituted
C6-10-arylaminocarbonyl, an optionally
substituted C6-10-aryl-C1-6-alkylaminocarbonyl or
an optionally substituted heteroarylamino-
carbonyl;
148
R6 denotes an optionally substituted
C1-10-alkylaminocarbonylamino,
C2-10-alkenylaminocarbonylamino or
C2-10-alkynylaminocarbonylamino, an optionally
substituted C3-8-cycloalkylaminocarbonylamino, an
optionally substituted C6-10-arylaminocarbonyl-
amino, an optionally substituted C6-10-aryl-
C1-6-alkylaminocarbonylamino or an optionally
substituted heteroarylaminocarbonylamino;
R6 denotes an optionally substituted
C1-10-alkyloxycarbonylamino,
C2-10-alkenyloxycarbonylamino or
C2-10-alkynyloxycarbonylamino, an optionally
substituted C3-8-cycloalkyloxycarbonylamino, an
optionally substituted C6-10-aryloxycarbonyl-
amino, an optionally substituted C6-10-aryl-
C1-6-alkyloxycarbonylamino or an optionally
substituted heteroaryloxycarbonylamino;
R5 denotes an optionally substituted
C1-10-alkylaminocarbonyloxy,
C2-10-alkenylaminocarbonyloxy or
C2-10-alkynylaminocarbonyloxy, an optionally
substituted C3-8-cycloalkylaminocarbonyloxy, an
optionally substituted C6-10-arylamino-
carbonyloxy, an optionally substituted
C6-10-aryl-C1-6-alkylaminocarbonyloxy or an
optionally substituted heteroarylamino-
carbonyloxy;
R6 denotes an optionally substituted C1-10-alkyl-N-
amidino, C2-10-alkenyl-N-amidino or C2-10-alkynyl-
N-amidino, an optionally substituted
C3-8-cycloalkyl-N-amidino, an optionally
substituted C6-10-aryl-N-amidino, an optionally
substituted C6-10-aryl-C1-6-alkyl-N-amidino or an
optionally substituted heteroaryl-N-amidino;
149
R6 denotes an optionally substituted C1-10-alkyloxy,
C2-10-alkenyloxy or C2-10-alkynyloxy, an optionally
substituted C3-8-cycloalkyloxy, an optionally
substituted C6-10-aryloxy, an optionally
substituted C6-10-aryl-C1-6-alkyloxy or an
optionally substituted heteroaryloxy;
R6 denotes an optionally substituted
C1-10-alkylcarbonyl, an optionally substituted
C2-10-alkenylcarbonyl, an optionally substituted
C2-10-alkynylcarbonyl, an optionally substituted
C3-8-cycloalkylcarbonyl, an optionally
substituted C6-10-arylcarbonyl, an optionally
substituted C6-10 - aryl- C1-6-alkylcarbonyl;
R6 denotes a group A-CO- wherein A is as
hereinbefore defined;
R6 denotes an optionally substituted
C1-10-alkyloxycarbonyl, C2-10-alkenyloxycarbonyl or
C2-10-alkynyloxycarbonyl, an optionally
substituted C3-8-cycloalkyloxycarbonyl, an
optionally substituted C6-10-aryloxycarbonyl, an
optionally substituted C6-10-aryl-C1-6-
alkyloxycarbonyl or an optionally substituted
heteroaryloxycarbonyl;
R6 denotes an optionally substituted
C1-10-alkylcarbonyloxy, C2-10-alkenylcarbonyloxy or
C2-10-alkynylcarbonyloxy, an optionally
substituted C3-8-cycloalkylcarbonyloxy, an
optionally substituted C6-10-arylcarbonyloxy, an
optionally substituted C6-10-aryl-C1-6alkyl-
carbonyloxy or an optionally substituted
heteroarylcarbonyloxy;
150
R6 denotes an optionally substituted
C1-10-alkylthio, C2-10-alkenylthio or
C2-10-alkynylthio, an optionally substituted
C3-8-cycloalkylthio, an optionally substituted
C6-10-arylthio, an optionally substituted
C6-10-aryl-C1-6-alkylthio or an optionally
substituted heteroarylthio;
R6 denotes an optionally substituted
C1-10-alkylcarbonyloxy-C1-6-alkyl,
C2-10-alkenylcarbonyloxy-C1-6-alkyl or
C2-10-alkynylcarbonyloxy-C1-6-alkyl, an optionally
substituted C3-8-cycloalkylcarbonyloxy-C1-6-alkyl,
an optionally substituted C6-10-arylcarbonyloxy-
C1-6-alkyl, C6-10-aryl-C1-6-alkylcarbonyloxy-
C1-6-alkyl or heteroarylcarbonyloxy-C1-6-alkyl;
R6 denotes an optionally substituted group of the
formula
R10O-B-(CH2)n~
wherein n=1, 2, 3 or 4, where B denotes a
C6-10-aryl or a single bond;
R6 denotes an optionally substituted amine,
preferably NR8R9;
R6 denotes an optionally substituted group of the
formula
151
<IMG>
<IMG>
<IMG>
R6 denotes an optionally substituted group of the
formula
<IMG>
<IMG>
<IMG>
<IMG> <IMG>
wherein Y is a single bond or an alkylene, an
alkenylene or an alkynylene having up to 6,
preferably 4 carbon atoms in the chain;
R6 is an optionally substituted group of the
formula
152
<IMG> <IMG>
<IMG>
<IMG>
wherein Y is a single bond or an alkylene, an
alkenylene or an alkynylene having up to 6,
preferably 4 carbon atoms in the chain;
R3 denotes hydrogen, an optionally substituted
C3-6-cycloalkyl group, a branched or unbranched
alkyl, alkenyl or alkynyl group having up to 10
carbon atoms, preferably an alkyl group having 1
to 4 carbon atoms which may optionally be
substituted by hydroxy, phenyl, substituted
phenyl, benzyl, substituted benzyl, amino,
substituted amino or C1-8-alkyloxy, preferably
C1-4-alkyloxy, or -(CH2)m-NHCOOR10 wherein m = 1,
2, 3 or 4;
R8 denotes a 5-, 6- or 7-membered heterocyclic
group which is carbon linked directly or via a
C1-4-alkyl chain and which contains one or more
heteroatoms selected from the group comprising
nitrogen, oxygen or sulphur and may optionally
be mono- or polysubstituted, preferably
monosubstituted, by benzyl, optionally
substituted benzyl, C1-4-alkyl, halogen, -OR10,
-CN, -NO2, -NH2, -OH, =O, -COOH, -SO3H or -COOR10;
R8 denotes a bicyclic heterocyclic group which is
C-linked directly or via a C1-4-alkyl chain and
which contains one or more heteroatoms selected
from the group comprising nitrogen, oxygen or
153
sulphur and is optionally mono- or
polysubstituted, preferably monosubstituted, by
benzyl, optionally substituted benzyl,
C1-4-alkyl, halogen, -OR10, - CN, -NO2, -NH2, -OH,
=O, -COOH, -SO3H, - COOR10;
R9 denotes hydrogen, an optionally substituted
C3-6-cycloalkyl group, a branched or unbranched
alkyl, alkenyl or alkynyl group having up to 10,
preferably 1 to 4 carbon atoms, which may
optionally be substituted by hydroxy, phenyl,
substituted phenyl, benzyl, substituted benzyl,
amino, substituted amino, C1-8-, preferably
C1-4-alkoxy, or -(CH2)m-NHCOOR10 wherein m equals
1, 2, 3 or 4;
R9 denotes a 5-, 6- or 7-membered heterocyclic
group which is carbon linked directly or via a
C1-4-alkyl chain and which contains one or more
heteroatoms selected from the group comprising
nitrogen, oxygen or sulphur and may optionally
be mono- or polysubstituted, preferably
monosubstituted, by benzyl, optionally
substituted benzyl, C1-4-alkyl, halogen, -OR10,
- CN, - NO2, NH2, - OH, =O, -COOH, -SO3H or -COOR10;
R9 denotes a bicyclic heterocyclic group which is
C-linked directly or via a C1-4-alkyl chain and
which contains one or more heteroatoms selected
from the group comprising nitrogen, oxygen or
sulphur and is optionally mono- or
polysubstituted, preferably monosubstituted, by
benzyl, optionally substituted benzyl,
C1-4-alkyl, halogen, -OR10, -CN, -NO2, -NH2, -OH,
=O, - COOH, - SO3H, - COOR10;
or
R8 and R9 together with the nitrogen atom form a
saturated or unsaturated 5- or 6-membered ring
154
which may contain as further heteroatoms
nitrogen, oxygen or sulphur, whilst the
heterocyclic group may be substituted by a
branched or unbranched alkyl group having 1 to 4
carbon atoms, preferably methyl, or may carry
one of the following groups
-(CH2)n-phenyl,
-(CH2)n-NH2, =O, a ketal - preferably
-O-CH2-CH2-O-
-(CH2)nNH-C1-4-alkyl,
- (CH2)n-N(C1-8-alkyl) 2,
-(CH2)n-NHCOOR10, (n = 2, 3, 4), halogen,
-OR10, -CN, -NO2, -NH2, -CH2NR8R9,
- OH, - COOH, - SO3H, - COOR10, - CONR8R9, - SO2-R10;
R10 denotes hydrogen, C1-4-alkyl, C2-4-alkenyl,
C2-4-alkynyl, a benzyl or phenyl group which is
optionally mono- or polysubstituted by OCH3,
optionally in the form of the racemates, the
enantiomers and diastereomers thereof and their
mixtures, as well as optionally the
pharmacologically acceptable acid addition salts
thereof.
2. Compounds of general formulae (Ia) to (Id)
<IMG>
<IMG>
155
<IMG> <IMG>
wherein
R1 or R3 denotes hydrogen, C1-4-alkyl or benzyl;
R2 denotes hydrogen, a C1-8-alkyl, C2-8-alkenyl or
C2-8-alkynyl group which may optionally be
substituted, by -CN, -CH2NR8R9, -OH
(polysubstitution also possible), -OR10, -NR8R9,
-NHCOR10, -NHCONR8R9, -NHCOOR10, halogen, -OCOR10,
-OCO-pyridyl, -OCH2COOH, -OCH2COOR10, -SO2R7,
-S-R7, -NHCONH-phenyl, -OCH2-CONR8R9, -OCH2CH2OH,
-SO2-CH2-CH2-O-COR10, -OCH2-CH2-NR8R9,
-SO2-CH2-CH2-OH, -CONHSO2R10, -CH2CONHSO2R10,
-OCH2CH2OR10, -COOH, -COOR10, -CONR8R9, -CHO, -SR10,
-SOR10, -SO2R10, -SO3H, -SO2NR8R9, -OCH2-CH2OCOR10,
-CH=NOH -CH=NOR10, =O, -COR11, -CH(OH)R11,
-CH(OR10)2, -CH=CH-R12, OCONR3R9, optionally
mono- or poly-substituted, preferably mono-methyl-
substituted 1,3-dioxolane or 1,3-dioxane;
R2 denotes phenyl-C1-6-alkyl, phenyl-C2-6-alkenyl or
phenyl-C2-6-alkynyl, wherein the phenyl ring is
optionally substituted either directly or via a
C1-4-alkylene bridge by one or more, of the group
C1-3-alkyl, -CN, -NR8R9, -NO2, -OH, -OR10,
-CH2-NH-SO2-R10, -NHCOR10, -NHCONR8R9, halogen,
-OCOR10, -OCO-pyridyl, -OCH2COOH, -OCH2COOR10,
-CH20COR10, -SO2R7, -OCH2-CONR8R9, -OCH2CH2OH,
-OCH2-CH2-NR8R9, -CONHSO2R10, -OCH2CH2OR10, -COOH,
-COOR10, -CF3, cyclopropyl, -CONR8R9, -CH2OH,
-CH2OR10, -CHO, -SR10, -SOR10, -SO2R10, -SO3H
156
-SO2NR8R9, -OCH2-CH2OCOR10, -CH=NOH, -CH=NOR10,
-COR11, -CH(OH)R11, -CH(OR10) 2, -NHCOOR10,
-CH2CONHSO2R10, -CH=CH-R12, -OCONR8R9,
-CH2-O-CONR8R9, -CH2-CH2-O-CONR8R9, optionally
mono- or poly-methyl-substituted 1,3-dioxolane
or 1,3-dioxane;
R2 denotes C3-7-cycloalkyl-C1-6-alkyl,
C3-7-cycloalkyl-C2-6-alkenyl, C3-7-cycloalkyl-
C2-6-alkynyl, wherein the cycloalkyl group is
optionally substituted either directly or via a
C1-4-alkylene bridge by one or more, of the
groups -CN, -NR8R9, =O, -OH, -OR10, -NR8R9,
-NHCOR10, -NHCONR8R9, halogen, -OCOR10,
-OCO-pyridyl, -OCH2COOH, -OCH2COOR10, -CH2OCOR10,
-SO2R7, -OCH2-CONR8R9, -OCH2CH2OH, -OCH2-CH2-NR8R9,
-OCH2CH2OR10, -COOH, -COOR10, -CONR8R9, -CH2OH,
-CH2OR10, -CHO, -SR10, -SOR10, -SO2R10, -SO3H,
-SO2NR8R9, -OCH2-CH2OCOR10, -CH=NOH, -CH=NOR10,
-COR11, -CH(OH)R11, -CONHSO2R10, -CH(OR10)2,
-NHCOOR10, -CH=CH-R12, -OCONR8R9, -CH2-O-CONR8R9,
-CH2-CH2-O-CONR8R9, methyl-substituted 1,3-
dioxolane or 1,3-dioxane;
R2 denotes a group of the formula
A-C1-6-alkyl, A-CONH-C1-6-alkyl,
A-CONH-C26-alkenyl, A-CONH-C26-alkynyl,
A-NH-CO-Cl6-alkyl, A-NH-CO-C26-alkenyl,
A-NH-CO-C26-alkynyl, A-C26-alkenylene,
A-C2-6-alkynylene or A-, wherein A is a C- or
N-linked 5-, 6- or 7-membered heterocyclic group
which contains one or more heteroatoms from the
group comprising nitrogen, oxygen or sulphur and
may optionally be mono- or poly-substituted by
benzyl, optionally substituted benzyl,
C1-4-alkyl, halogen, -OR10, -CN, -NO2, -NH2,
-CH2NR8R9, -OH, =O, a ketal, ethyleneketal,
157
-COOH, -SO3H, -COOR10, -CON8R9, -COR11, -SO-R10 or
-CONR8R9;
R2 denotes C3-7-cycloalkyl, which may optionally be
substituted by =O, -OH, -OR10, -OCOR10 or
-OCO-pyridyl;
R2 denotes phenyl which is optionally substituted
by -OH, halogen, -OR10, C1-4-alkyl, -NH2, -COOH,
-SO3H, -COOR10, -OCH2COOR10, -CN or -OCH2CONR8R9;
R2 denotes a norbornane, norbornene,
C3-6-dicycloalkylmethyl, preferably
dicyclopropylmethyl, adamantane or noradamatane
group optionally substituted by C1-4-alkyl;
R2 denotes -CH=CH-phenyl in which the phenyl ring
is mono- or polysubstituted by methoxy, hydroxy
or halogen;
R2 is a [3.3.0]-bicyclooctane;
R2 is a C-linked piperidine or furan;
R2 is an amine of general formula NR8R9;
R4 or R5 denotes hydrogen, an optionally branched
C1-8-alkyl, C2-8-alkenyl or C2-8-alkynyl group
which is substituted by -CN, -CH2NR8R9, -OH
(polysubstitution also possible), -OR10, -NR8R9,
-NHCOR10, -NHCONR8R9, halogen, -OCOR10,
-OCO-pyridyl, -OCH2COOH, -OCH2COOR10, -SO2R7,
-S-R7, -NHCONH-phenyl, -OCH2-CONR8R9, -OCH2CH2OH,
-SO2-CH2-CH2-O-COR10, -OCH2-CH2-NR8R9,
-SO2-CH2-CH2-OH, -CONHSO2R10, -CH2CONHSO2R10,
-OCH2CH2OR10, -COOH, -COOR10, -CONR8R9, -CHO, -SR10,
-SOR10, -SO2R10, -SO3H, -SO2NR8R9, -OCH2-CH2OCOR10,
158
=O, -CH=NOH -CH=NOR10, -COR11, -CH(OH)R11,
-CH (OR10)2, -CH=CH-R12, -OCONR8R9, optionally
mono- or poly-, methyl-substituted 1,3-dioxolane or
1,3-dioxane;
R4 or R5 denotes phenyl-C1-6-alkyl, phenyl-C2-6-alkenyl or
phenyl-C2-6-alkynyl, wherein the phenyl ring is
optionally substituted either directly or via a
C1-4-alkylene bridge by one or more, preferably
one of the groups, -C1-3- alkyl, - CN, -NR8R9, -NO2,
-OH, -OR10, -CH2-NH-SO2-R10, -NHCOR10, -NHCONR8R9,
halogen, -OCOR10, -OCO-pyridyl, -OCH2COOH,
-OCH2COOR10, -CH20COR10, - SO2R7, -OCH2-CONR8R9,
-OCH2CH2OH, -OCH2-CH2-NR8R9, -CONHSO2R10,
-OCH2CH2OR10, -COOH, -COOR10, -CF3, cyclopropyl,
-CONR8R9, -CH2OH, -CH2OR10, -CHO, -SR10, -SOR10,
-SO2R10, -SO3H, -SO2NR8R9, -OCH2-CH2OCOR10, -CH=NOH,
-CH=NOR10, -COR11, -CH(OH)R11, -CH(OR10) 2,
-NHCOOR10, -CH2CONHSO2R10, -CH=CH-R12, -OCONR8R9,
-CH2-O-CONR8R9, -CH2-CH2-O-CONR8R9, optionally
mono- or poly-, methyl-substituted 1,3-dioxolane
or 1,3-dioxane;
R4 or R5 denotes an optionally substituted C3-7-cycloalkyl
group;
R4 or R5 denotes C3-7-cycloalkyl-C1-6-alkyl,
C3-7-cycloalkyl-C2-6-alkenyl, C3-7-cycloalkyl-
C2-6-alkynyl, wherein the cycloalkyl group is
optionally substituted either directly or via a
C1-4-alkylene bridge by -CN, -NR8R9, =O, - OH,
-OR10, -NR8R9, -NHCOR10, -NHCONR8R9, halogen,
-OCOR10, -OCO-pyridyl, -OCH2COOH, -OCH2COOR10,
-CH2OCOR10, -SO2R7, -OCH2-CONR8R9, -OCH2CH2OH,
-OCH2-CH2-NR8R9, -OCH2CH2OR10, -COOH, -COOR10,
-CONR8R9, -CH2OH, -CH2OR10, -CHO, -SR10, -SOR10,
-SO2R10, -SO3H, -SO2NR8R9, -OCH2-CH2OCOR10, -CH=NOH,
-CH=NOR10, -COR11, -CH(OH)R11, -CONHSO2R10,
159
-CH(OR10)2, -NHCOOR10, -CH=CH-R12, -OCONR8R9,
-CH2-O-CONR8R9, -CH2-CH2-O-CONR8R9, optionally
mono- or poly-, methyl-substituted 1,3-dioxolane
or 1,3-dioxane;
R4 or R5 denotes a group of the formula
A-C1-6-alkyl, A-CONH-C1-6-alkyl,
A-CONH-C2-6-alkenyl, A-CONH-C2-6-alkynyl,
A-NH-CO-C1-6-alkyl, A-NH-CO-C2-6-alkenyl,
A-NH-CO-C2-6-alkynyl, A-C2-6-alkenyl or
A-C2-6-alkynyl, wherein A is a C- or N-linked
heterocyclic group which contains one or more
heteroatoms selected from the group comprising
nitrogen, oxygen or sulphur and may optionally
be mono- or polysubstituted by C1-4-alkyl,
halogen, -OR10, -CN, -NO2, -NH2, -CH2NR8R9, -OH,
=O, a ketal, ethyleneketal, -COOH, -SO3H,
-COOR10, -CONR8R9, -COR11, -SO2-R10 or -CONR8R9;
R6 denotes hydrogen, a C1-8-alkyl, C2-8-alkenyl or
C2-8-alkynyl group which is substituted by -CN,
-CH2NR8R9, -OH (polysubstitution also possible),
-OR10, -NR8R9 -NHCOR10, -NHCONR8R9, -NHCOOR10,
halogen, -OCOR10, -OCO-pyridyl, -OCH2COOH,
-OCH2COOR10, -SO2R7, -S-R7, -NHCONH-phenyl,
-OCH2-CONR8R9, -OCH2CH2OH, -SO2-CH2-CH2-O-COR10,
-OCH2-CH2-NR8R9, -SO2-CH2-CH2-OH, -CONHSO2R10,
-CH2CONHSO2R10, -OCH2CH2OR10, -COOH, -COOR10,
-CONR8R9, -CHO, -SR10, -SOR10, -SO2R10, -SO3H,
-SO2NR8R9, -OCH2-CH2OCOR10, -CH=NOH, -CH=NOR10,
-COR11, -CH(OH)R11, -CH(OR10)2, -CH=CH-R12,
-OCONR8R9, optionally mono- or poly-, methyl-
substituted 1,3-dioxolane or 1,3-dioxane;
R6 denotes phenyl-C1-6-alkyl, phenyl-C2-6-alkenyl or
phenyl-C2-6-alkynyl, wherein the phenyl ring is
optionally substituted either directly or via a
160
C1-4-alkylene bridge by one or more of the
groups, C1-3-alkyl, - CN, NR8R9, -NO2, -OH, -OR10,
-CH2-NH-SO2-R10, -NHCOR10, -NHCONR8R9, halogen,
-OCOR10, -OCOpyridyl, -OCH2COOH, -OCH2COOR10,
-CH2OCOR10, -SO2R7, - OCH2-CONR8R9, -OCH2CH2OH,
-OCH2-CH2-NR8R9, -CONHSO2R10, -OCH2CH2OR10, -COOH,
-COOR10, -CF3, cyclopropyl, -CONR8R9, -CH2OH,
-CH2OR10, -CHO, -SR10, - SOR10, -SO2R10, -SO3H,
-SO2NR8R9, -OCH2-CH2OCOR10, -CH=NOH, - CH=NOR10,
-COR11, -CH(OH)R11, -CH(OR10)2, -NHCOOR10,
-CH2CONHSO2R10, -CH=CH-R12, -OCONR8R9,
-CH2-O-CONR8R9, -CH2-CH2-O-CONR8R9, -CO-R10,
-CO-C1-4-alkyl-NR8R9, optionally mono- or
poly-methyl-substituted 1,3-dioxolane or 1,
3-dioxane;
R6 denotes C3-7-cycloalkyl-C1-6-alkyl,
C3-7-cycloalkyl-C2-6-alkenyl or C3-7-cycloalkyl-
C2-6-alkynyl, wherein the cycloalkyl group is
optionally substituted either directly or via a
C1-4-alkylene bridge by one or more of the groups
-CN -NR8R9, =O, -OH, -OR10, -NR8R9, -NHCOR10,
-NHCONR8R9, halogen, -OCOR10, -OCO-pyridyl,
-OCH2COOH, -OCH2COOR10, -CH2OCOR10, -SO2R7,
-OCH2-CONR8R9, -OCH2CH2OH, -OCH2-CH2-NR8R9,
-OCH2CH2OR10, -COOH, -COOR10, -CONR8R9, -CH2OH,
-CH2OR10, -CHO, -SR10, - SOR10, - SO2R10, -SO3H,
-SO2NR8R9, -OCH2-CH2OCOR10, -CH=NOH, -CH=NOR10,
-COR11, -CH(OH)R11, -CONHSO2R10, -CH (OR10)2,
-NHCOOR10, -CH=CH-R12, -OCONR8R9, -CH2-O-CONR8R9,
-CH2-CH2-O-CONR8R9 or methyl-substituted
1,3-dioxolane or 1,3-dioxane;
R6 denotes a group of the formula
A-C1-6-alkyl, A-CONH-C1-6-alkyl,
A-CONH-C2-6-alkenyl, A-CONH-C2-6-alkynyl,
A-NH-CO-C1-6-alkyl, A-NH-CO-C2-6-alkenyl,
161
A-NH-CO-C2-6-alkynyl, A-C2-6-alkenyl or
A-C2-6-alkynyl or A-,
wherein A is a C- or N-linked 5-, 6- or
7-membered heterocyclic group which contains one
or more heteroatoms from the group comprising
nitrogen, oxygen or sulphur and may optionally
be mono- or polysubstituted by benzyl,
optionally substituted benzyl, C1-4-alkyl,
halogen, -OR10, -CN, -NO2, -NH2, -CH2NR8R9, -OH,
=O, a ketal, ethyleneketal, -COOH, -SO3H,
-COOR10, -CONR8R9, -COR11, -SO2-R10 or -CONR8R9;
R6 denotes -CHO, -COOR10, -CONR8R9;
R6 denotes C3-7-cycloalkyl optionally substituted by
=O, -OH, -OR10, -OCOR10 or -OCO-pyridyl;
R6 denotes phenyl optionally substituted by -OH,
halogen, -OR10, C1-4-alkyl, preferably -CH3, -NH2,
-COOH, -SO3H, -COOR10, -OCH2COOR10, -CN or
-OCH2CONR8R9;
R6 denotes a norbonane, norbornene, C3-6-dicyclo-
alkylmethyl, preferably dicyclopropylmethyl,
adamantane or noradamantane group optionally
substituted by C1-4-alkyl;
R6 denotes -CH=CH-phenyl, wherein the phenyl ring
may be mono- or polysubstituted by methoxy,
hydroxy or halogen;
R6 denotes a [3.3.0]-bicyclooctane;
R6 denotes a C-linked piperidine or furan;
R7 denotes C1-4-alkyl which is optionally
substituted by -OH, -OCOR10, -OCO-pyridyl, -NH2,
162
-NR8R9 or -NHCOR10, preferably -CH2-CH2-OH,
-CH2CH2OCOR10, -CH2-CH2-CH2-OH or -CH2-CH2CH2OCOR10;
R8 denotes hydrogen, an optionally substituted
C3-6-cycloalkyl group, a branched or unbranched
alkyl, alkenyl or alkynyl group having up to 10
carbon atoms, which may optionally be
substituted by hydroxy, phenyl, substituted
phenyl, benzyl, substituted benzyl, amino,
substituted amino or C1-8-alkoxy, preferably
C1-4-alkoxy, or -(CH2)m-NHCOOR10 where m = 1, 2, 3
or 4;
R8 denotes a 5-, 6- or 7-membered heterocyclic
group which is C-linked directly or via a
C1-4-alkyl chain, and which contains one or more
heteroatoms selected from the group comprising
nitrogen, oxygen or sulphur and may optionally
be mono- or polysubstituted by benzyl,
optionally substituted benzyl, C1-4-alkyl,
halogen, -OR10, -CN, -NO2, -NH2, -OH, =O, - COOH,
-SO3H or -COOR10;
R3 denotes a bicyclic heterocyclic group C-linked
directly or via a C1-4-alkyl chain, which
contains one or more heteroatoms from the group
comprising nitrogen, oxygen or sulphur and may
optionally be mono- or polysubstituted, by
benzyl, optionally substituted benzyl,
C1-4-alkyl, halogen, -OR10, -CN, -NO2, -NH2, -OH,
=O, - COOH, - SO3H or -COOR10;
R9 denotes hydrogen, an optionally substituted
C3-6-cycloalkyl group, a branched or unbranched
alkyl, alkenyl or alkynyl group having up to 10
carbon atoms, which may optionally be
substituted by hydroxy, phenyl, substituted
phenyl, benzyl, substituted benzyl, amino,
163
substituted amino or C1-8-alkoxy, preferably
C1-4-alkoxy, or -(CH2)m-NHCOOR10 wherein m is 1, 2,
3 or 4;
R9 denotes a 5-, 6- or 7-membered heterocyclic
group which is C-linked directly or via a
C1-4-alkyl chain, and which contains one or more
heteroatoms selected from the group comprising
nitrogen, oxygen or sulphur and may optionally
be mono- or polysubstituted, by benzyl,
optionally substituted benzyl, C1-4-alkyl,
halogen, -OR10, -CN, -NO2, -NH2, -OH, =O, -COOH,
-SO3H or -COOR10;
R9 denotes a bicyclic heterocyclic group C-linked
directly or via a C1-4-alkyl chain, which
contains one or more heteroatoms from the group
comprising nitrogen, oxygen or sulphur and may
optionally be mono- or polysubstituted, by
benzyl, optionally substituted benzyl,
C1-4-alkyl, halogen, -OR10, -CN, -NO2, -NH2, -OH,
=O, -COOH, -SO3H or -COOR10,
or
R8 and R9 together with the nitrogen atom form a
saturated or unsaturated 5- or 6-membered ring
which may contain nitrogen, oxygen or sulphur as
additional heteroatoms, whilst the heterocyclic
group may be substituted by a branched or
unbranched C1-4-alkyl group, or may carry one of
the following groups:
- (CH2)n-phenyl,
- (CH2)n-NH2, =O, a ketal - preferably
-O-CH2-CH-O-,
- (CH2)nNH-C1-4-alkyl,
- (CH2)n-N(C1-8-alkyl)2,
- (CH2)n-NHCOOR10, (n = 1, 2, 3, 4), halogen,
-OR10, -CN, -NO2, -NH2, -CH2NR8R9,
164
-OH -COOH, -SO3H, -COOR10, -CONR8R9, -SO2-R10;
R10 denotes hydrogen, C1-4-alkyl, C2-4-alkenyl,
C2-4-alkynyl, a benzyl or phenyl group which is
optionally mono- or polysubstituted by OCH3;
R11 denotes C1-4-alkyl, C2-4-alkenyl, C2-4-alkynyl,
optionally substituted phenyl, optionally
substituted benzyl or C3-6-cycloalkyl;
R12 denotes -COOR10, -CH2OR10, -CONR8R9, hydrogen,
C1-3-alkyl, optionally substituted phenyl or
-CH2NR8R9,
optionally in the form of the racemates,
enantiomers and diastereomers thereof and
mixtures thereof, and optionally the
pharmacologically acceptable acid addition salts
thereof.
3. Compounds of general formulae (Ia) to (Id)
<IMG> <IMG>
<IMG>
<IMG>
wherein
R1 or R3 denotes hydrogen, C1-4-alkyl or benzyl;
165
R2 denotes hydrogen, C1-8-alkyl, preferably
C1-6-alkyl;
R2 denotes phenyl which is optionally substituted
by halogen, C1-4-alkyl, C1-4-alkyloxy, hydroxy or
NR8R9;
R2 denotes phenyl-C1-6-alkyl, phenyl-C2-6-alkenyl or
phenyl-C2-6-alkynyl, wherein the phenyl ring is
optionally substituted by halogen, preferably
fluorine or chlorine, C1-4-alkyl, C1-4-alkyloxy,
hydroxy or NR8R9;
R2 denotes an amine of formula NR8R9;
R2 denotes a 5- or 6-membered heterocyclic group
which is optionally C- or N-linked either
directly or via a C1-4-alkylene bridge,
containing one or more heteroatoms selected from
the group comprising nitrogen or oxygen and
optionally substituted by benzyl or C1-4-alkyl;
R2 denotes a C3-6-cycloalkyl which may optionally be
substituted by =O, hydroxy, C1-4-alkyl or
C1-4-alkyloxy;
R2 denotes norbornane, norbornene, adamantane or
noradamantane optionally substituted by
C1-4-alkyl;
R4 or R5 denotes hydrogen, C1-8-alkyl, phenyl-C1-4-alkyl,
phenyl-C2-6-alkenyl or phenyl- C2-6-alkynyl,
wherein the phenyl ring is optionally
substituted by halogen, hydroxy, C1-4-alkyl,
C1-4-alkyloxy or NR8R9;
166
R6 denotes hydrogen, C1-8-alkyl, wherein the alkyl
chain may be substituted by halogen, hydroxy,
=O, C1-4-alkyloxy, NR8R9, phenyloxy, -O-phenyl-
C1-4-alkyloxy, benzyloxy, -O-benzyl-O-
C1-4-alkyloxy, -OCO-C1-4-alkyl, -OCO-phenyl,
-OCO-benzyl, -OCO-pyridyl, -O-C2-4-alkylene,
-CO-C1-4-alkyl, -CHO, =NOH, -COOH, -COO-C1-4-alkyl,
-COO-phenyl, -COO-benzyl, -CONR8R9,
-NHCO-C1-4-alkyl, -NHCO-phenyl,
-CO-C1-4-alkyl-NR8R9, -SO2OH, -SO2-C1-4-alkyl or
-SO2-phenyl;
R6 denotes phenyl which may optionally be
substituted by halogen, hydroxy, C1-4-alkyl,
C1-4-alkyloxy, benzyloxy, phenyloxy, -NR8R9,
-OCO-C1-4-alkyl, -OCO-phenyl, -OCO-benzyl,
-OCO-pyridyl, -O-C2-4-alkylene, -CO-C1-4-alkyl,
-C1-4-alkyl-NH2, -C1-4- alkyl-OH, -C1-4-alkyl=NOH,
-COOH, -COO-C1-4-alkyl, -COO-phenyl, -COO-benzyl,
-CONR8R9, -CO-C1-4-alkyl-NH2, -SO2OH,
-SO2-C1-4-alkyl or -SO2-phenyl;
R6 denotes phenyl-C1-4-alkyl, phenyl-C2-6-alkenyl or
phenyl-C2-6-alkynyl, wherein the phenyl ring may
optionally substituted by halogen, hydroxy,
C1-4-alkyl, C1-4-alkoxy, benzyloxy, phenyloxy,
-NR8R9, -OCO-C1-4-alkyl, -OCO-phenyl, -OCO-benzyl,
-OCO-pyridyl, -O-C2-4-alkylene, -CO-C1-4-alkyl,
-C1-4-alkyl-NR8R9, -C1-4-alkyl-OH, -C1-4-alkyl=NOH,
-COOH, -COO-C1-4-alkyl, -COO-phenyl, -COO-benzyl,
-CONR8R9, -CO-C1-4-alkyl-NH2, -SO2OH,
-SO2-C1-4-alkyl or -SO2-phenyl;
R6 denotes a 5- or 6-membered heterocyclic group
optionally C- or N-linked either directly or via
a C1-4-alkylene bridge, which contains one, two
or three heteroatoms selected from nitrogen or
167
oxygen and is optionally mono- or
polysubstituted by benzyl or C1-4-alkyl;
R6 denotes a C3-6-cycloalkyl or C3-6-cycloalkyl-C1-4-alkyl
group which may optionally be
substituted by =O, hydroxy, C1-4-alkyl or
C1-4-alkyloxy;
R6 denotes norbornyl, norbornenyl, adamantyl or
noradamantyl optionally substituted by
C1-4-alkyl;
R6 denotes -CHO, -COOH, -COO-C1-4-alkyl,
-COO-phenyl, -COO-benzyl or -CONR8R9;
R6 denotes an amine of general formula NR8R9;
R8 denotes hydrogen, a branched or unbranched
C1-4-alkyl group;
R8 denotes a C-linked 5- or 6-membered heterocyclic
group which contains one, two or three
heteroatoms selected from the group comprising
nitrogen, oxygen and sulphur and is optionally
substituted by benzyl, C1-4-alkyl, C1-4-alkyloxy,
halogen, -CN, -NO2, -NH2, -OH or =O;
R9 denotes hydrogen, a branched or unbranched
C1-4-alkyl group;
R9 denotes a C-linked 5- or 6-membered heterocyclic
group which contains one, two or three
heteroatoms selected from the group comprising
nitrogen, oxygen or sulphur and is optionally
substituted by benzyl, C1-4-alkyl, C1-4-alkyloxy,
halogen, -CN, -NO2, -NH2, -OH or =O;
or
168
R8 and R9 together with the nitrogen atom form a
saturated or unsaturated 5- or 6-membered ring
which may contain nitrogen or oxygen as
additional heteroatoms, whilst the heterocyclic
group may be substituted by a branched or
unbranched C1-4-alkyl group, preferably methyl,
or by a -(CH2)1-4-phenyl group, preferably
benzyl,
optionally in the form of their racemates,
enantiomers, diastereomers and mixtures thereof,
and optionally the pharmacologically acceptable
acid addition salts thereof.
4. Compounds of general formulae (Ia) and (Ib)
<IMG>
<IMG>
wherein
R1 or R3 denotes hydrogen, C1-4-alkyl or benzyl;
R2 denotes hydrogen or C1-6-alkyl,
R2 denotes cyclopentyl, cyclohexyl, cyclopentanone,
cyclohexanone, hydroxycyclopentane or
hydrocyclohexane;
R2 denotes a morpholine group optionally
substituted by C1-4-alkyl, a piperidinyl group, a
piperazinyl group optionally substituted by
benzyl or C1-4-alkyl, pyridyl, tetrahydrofuranyl,
tetrahydropyranyl or furyl;
169
R2 denotes a phenyl group optionally substituted by
C1-4-alkyl, halogen or hydroxy;
R2 denotes a phenyl-C1-4-alkyl, wherein the phenyl
ring is optionally substituted by halogen,
preferably fluorine or chlorine, C1-4-alkyl,
C1-4-alkyloxy, hydroxy or NR8R9;
R2 denotes an amine of general formula NR8R9;
R2 denotes a norbornenyl, norbornyl, adamantyl or
noradamantyl optionally substituted by
C1-4-alkyl;
R4 denotes hydrogen, C1-7-alkyl, phenyl-C1-3-alkyl,
preferably benzyl, wherein the phenyl ring may
be substituted by halogen, hydroxy, C1-4-alkyl,
C1-4-alkyloxy or NR8R9;
R6 denotes hydrogen, C1-6-alkyl wherein the alkyl
chain may be substituted by halogen, hydroxy,
=O, C1-4-alkyloxy, NR8R9, phenyloxy, -O-phenyl-O-
C1-4-alkyloxy, benzyloxy,
-O-benzyl-O-C1-4-alkyloxy, -OCO-C1-4-alkyl,
-OCO-phenyl, -OCO-pyridyl, -OCO-benzyl,
-O-C2-4-alkylene, -CO-C1-4-alkyl, -CHO, =NOH, -COOH,
-COO-C1-4-alkyl; -COO-phenyl, -COO-benzyl,
-CONR8R9, -NHCO-C1-4-alkyl, -NHCO-phenyl,
-CO-C1-4-alkyl-NR8R9, -SO2OH, -SO2-C1-4-alkyl or
-SO2-phenyl;
R6 denotes phenyl, wherein the phenyl ring may be
substituted by halogen, hydroxy, C1-4-alkyl,
C1-4-alkyloxy or NR8R9;
R6 denotes phenyl-C1-3-alkyl, wherein the phenyl
ring may be substituted by halogen, preferably
fluorine or chlorine, hydroxy, C1-4-alkyl,
170
C1-4-alkyloxy, benzyloxy, phenyloxy, -NR8R9,
-OCO-C1-4-alkyl, -OCO-phenyl, -OCO-benzyl,
-OCO-pyridyl, -O-C2-4-alkylene, -CO-C1-4-alkyl,
-C1-4-alkyl-NR8R9, -C1-4-alkyl-OH, -C1-4-alkyl=NOH,
-COOH, -COO-C1-4-alkyl, -COO-phenyl, -COO-benzyl,
-CONR8R9, -CO-C1-4-alkyl-NR8R9, -SO2OH,
-SO2-C1-4-alkyl or -SO2-phenyl;
R6 denotes a cyclopentyl, cyclohexyl, cyclohexyl-C1-3-alkyl,
preferably cyclohexylmethyl,
cyclopentanone, cyclohexanone,
hydroxycyclopentane or hydroxycyclohexane linked
via a single bond or via a C1-4-alkylene chain;
R6 denotes a furan, tetrahydrofuran, .alpha.-pyran,
.gamma.-pyran, dioxolane, tetrahydropyran, dioxane,
thiophene, thiolane, dithiolane, pyrrole,
pyrroline, pyrrolidine, pyrazole, pyrazoline,
imidazole, imidazoline, imidazolidine, triazole,
pyridine, piperidine, pyridazine, pyrimidine,
pyrazine, piperazine, triazine, morpholine,
thiomorpholine, oxazole, isoxazole, oxazine,
thiazole, isothiazole, thiadiazole, oxadiazole
or pyrazolidine linked via a single bond or via
a C1-4-alkylene chain;
R6 denotes -CHO, -COOH, -COO-C1-4-alkyl;
-COO-phenyl, -COO-benzyl, -CO-NH-C1-4-alkyl,
-CO-N(C1-4-alkyl)2 or -CO-NH-phenyl;
R6 denotes an amine of general formula NR8R9;
R8 denotes hydrogen, a branched or unbranched
C1-4-alkyl group;
R8 denotes a C-linked pyrrole, pyrroline,
pyrrolidine, pyrazole, pyrazoline, imidazole,
imidazoline, imidazolidine, triazole, pyridine,
171
piperidine, pyridazine, pyrimidine, pyrazine,
piperazine, morpholine, oxazole, isoxazole,
thiazole, isothiazole or thiadiazole optionally
substituted by chlorine, bromine, C1-4-alkyl,
C1-4-alkyloxy, -NO2, -NH2 or -OH;
R9 denotes hydrogen, a branched or unbranched
C1-4-alkyl group;
R9 denotes a C-linked pyrrole, pyrroline,
pyrrolidine, pyrazole, pyrazoline, imidazole,
imidazoline, imidazolidine, triazole, pyridine,
piperidine, pyridazine, pyrimidine, pyrazine,
piperazine, morpholine, oxazole, isoxazole,
thiazole, isothiazole or thiadiazole optionally
substituted by chlorine, bromine, C1-4-alkyl,
C1-4-alkyloxy, -NO2, -NH2, -OH,
or
R8 and R9 together with the nitrogen atom form a
saturated or unsaturated 5- or 6-membered ring
which may contain nitrogen or oxygen as
additional heteroatoms, wherein the heterocyclic
group may be substituted by a branched or
unbranched C1-4-alkyl group, or by a
-(CH2)1-4-phenyl group,
optionally in the form of the racemates, the
enantiomers and the diastereomers thereof and
mixtures thereof, and optionally the
pharmacologically acceptable acid addition salts
thereof.
5. Compounds of general formula (Ib)
<IMG>
172
wherein
R2 denotes hydrogen, C1-4-alkyl, phenyl, benzyl,
wherein the phenyl ring is optionally
substituted by fluorine, pyridyl, piperidinyl,
morpholinyl, piperazinyl, 4-benzylpiperazinyl,
furyl, tetrahydrofuranyl, tetrahydropyranyl,
NR8R9, cyclopentyl, cyclohexyl, adamantyl,
noradamantyl, norbornyl or norbornenyl;
R3 denotes hydrogen, C1-3-alkyl or benzyl;
R4 denotes hydrogen, C1-5-alkyl or benzyl;
R6 denotes hydrogen, C1-4-alkyl, which may
optionally be substituted by OH, chlorine,
bromine, C1-4-alkyloxy or NR8R9, -CHO, -COOH,
-COO-C1-4-alkyl, phenyl, phenyl-C1-3-alkyl
optionally substituted by fluorine or benzyloxy,
optionally methoxy-substituted
phenyloxy-C1-3-alkyl, optionally
methoxy-substituted benzyloxy-C1-3-alkyl,
benzyloxybenzyl, benzoyloxymethyl,
pyridylcarbonyloxymethyl, cyclopentyl, furyl,
cyclohexylmethyl, pyridylmethyl, N-pyrrolyl-methyl,
or N-morpholinomethyl;
R8 denotes hydrogen, C1-4-alkyl or pyridyl;
R9 denotes hydrogen, C1-4-alkyl or pyridyl,
optionally in the form of the racemates, the
enantiomers and the diastereomers thereof and
mixtures thereof, and optionally the
pharmacologically acceptable acid addition salts
thereof.
6. Compounds of general formula (Ia)
173
<IMG>
wherein
R1 denotes hydrogen, C1-3-alkyl or benzyl;
R2 denotes hydrogen, C1-4-alkyl, phenyl, benzyl,
wherein the phenyl ring is optionally
fluorine-substituted, pyridyl, piperidinyl, morpholinyl,
piperazinyl, 4-benzylpiperazinyl, furyl,
tetrahydrofuranyl, tetrahydropyranyl, NR8R9,
cyclopentyl, cyclohexyl, adamantyl,
noradamantyl, norbornyl or norbornenyl;
R4 denotes hydrogen, C1-5-alkyl or benzyl;
R6 denotes hydrogen, C1-4-alkyl, which may
optionally be substituted by OH, chlorine,
bromine, C1-4-alkyloxy or NR8R9, -CHO, -COOH,
-COO-C1-4-alkyl, phenyl, phenyl-C1-3-alkyl
optionally substituted by fluorine or benzyloxy,
optionally methoxy-substituted
phenyloxy-C1-3-alkyl, optionally
methoxy-substituted benzyloxy-C1-3-alkyl,
benzyloxybenzyl, benzoyloxymethyl,
pyridylcarbonyloxymethyl, cyclopentyl, furyl,
cyclohexylmethyl, pyridylmethyl,
N-pyrrolylmethyl or N-morpholinomethyl;
R8 denotes hydrogen, C1-4-alkyl or pyridyl;
R9 may denote hydrogen, C1-4-alkyl or pyridyl,
174
optionally in the form of the racemates, the
enantiomers, the diastereomers thereof and
mixtures thereof and optionally the
pharmacologically acceptable acid addition salts
thereof.
7. Compounds of general formula (Ic)
<IMG>
wherein
R1 denotes hydrogen or C1-3-alkyl;
R2 denotes hydrogen, C1-4-alkyl, cyclopentyl,
cyclopentanone, hydroxycyclopentane, furan or
benzyl;
R5 denotes C1-6-alkyl;
R6 denotes hydrogen, benzyl or cyclopentyl,
optionally in the form of the racemates, the
enantiomers, the diastereomers and mixtures
thereof, and optionally the pharmacologically
acceptable acid addition salts thereof.
8. Compounds of general formula (Id)
<IMG>
175
wherein
R1 denotes hydrogen or C1-3-alkyl;
R2 denotes hydrogen, C1-4-alkyl, cyclopentyl,
cyclopentanone, hydroxycyclopentane, furan or
benzyl;
R5 denotes C1-6-alkyl;
R6 denotes hydrogen, benzyl or cyclopentyl,
optionally in the form of the racemates, the
enantiomers, the diastereomers and mixtures
thereof, and optionally the pharmacologically
acceptable acid addition salts thereof.
9. Compounds of general formula (Ib)
<IMG>
wherein
R2 denotes hydrogen, methyl, ethyl, n-propyl,
i-propyl, n-butyl, tert.-butyl, phenyl, benzyl,
4-fluorobenzyl, pyridyl, N-piperidinyl,
N-morpholinyl, N-piperazinyl, 4-benzylpiperazinyl,
2-furyl, 3-tetrahydrofuranyl,
4-tetrahydropyranyl, -NMe2, cyclopentyl,
cyclohexyl, adamantan-1-yl, noradamantan-3-yl,
norbornan-2-yl or 5-norbornen-2-yl;
R3 denotes hydrogen, methyl, ethyl, n-propyl or
benzyl;
176
R4 denotes hydrogen, methyl, ethyl, n-propyl,
i-propyl, n-butyl, tert.-butyl, n-pentyl or
benzyl;
R6 denotes hydrogen, methyl, ethyl, n-propyl,
i-propyl, n-butyl, tert.-butyl, phenyl, benzyl,
cyclopentyl, 2-furyl, 2-pyridylmethyl,
3-pyridylmethyl, 4-pyridylmethyl,
cyclohexylmethyl, phenylethyl, N-morpholinomethyl,
N-pyrrolylmethyl, (3-pyridyl)-NH-CH2-,
Ph-CO-O-CH2-, pyridyl-CO-O-CH2-, Ph-O-CH2-,
(4-MeO-Ph)-O-CH2-, (4-MeO-Ph)-CH2-O-CH2-,
(4-Ph-CH2-O-Ph)-CH2-, 4-F-Ph-CH2-, 3,4-F-Ph-CH2-,
-COOH, -COOMe, -CH2-OH, -CH2-OMe, -CH2OEt or
-CH2-NMe2,
optionally in the form of the racemates, the
enantiomers, the diastereomers and mixtures
thereof and optionally the pharmacologically
acceptable acid addition salts thereof.
10. Compounds of general formula (Ia)
<IMG>
wherein
R1 denotes hydrogen, methyl, ethyl, n-propyl or
benzyl;
R2 denotes hydrogen, methyl, ethyl, n-propyl,
i-propyl, n-butyl, tert.-butyl, phenyl, benzyl,
4-fluorobenzyl, pyridyl, N-piperidinyl,
N-morpholinyl, N-piperazinyl, 4-benzylpiperazinyl,
2-furyl, 3-tetrahydrofuranyl,
177
4-tetrahydropyranyl, -NMe2, cyclopentyl,
cyclohexyl, adamantan-1-yl, noradamantan-3-yl,
norbornan-2-yl or 5-norbornen-2-yl;
R4 denotes hydrogen, methyl, ethyl, n-propyl,
i-propyl, n-butyl, tert.-butyl, n-pentyl or
benzyl;
R6 denotes hydrogen, methyl, ethyl, n-propyl,
i-propyl, n-butyl, tert.-butyl, phenyl, benzyl,
cyclopentyl, 2-furyl, 2-pyridylmethyl,
3-pyridylmethyl, 4-pyridylmethyl,
cyclohexylmethyl, phenylethyl, N-morpholinomethyl,
N-pyrrolylmethyl, (3-pyridyl)-NH-CH2-,
Ph-CO-O-CH2-, pyridyl-CO-O-CH2-, Ph-O-CH2-,
(4-MeO-Ph)-O-CH2-, (4-MeO-Ph)-CH2-O-CH2-,
(4-Ph-CH2-O-Ph)-CH2-, 4-F-Ph-CH2-, 3,4-F-Ph-CH2-,
-COOH, -COOMe, -CH2-OH, -CH2-OMe, -CH2OEt or
-CH2-NMe2,
optionally in the form of the racemates, the
enantiomers, the diastereomers and mixtures
thereof and optionally the pharmacologically
acceptable acid addition salts thereof.
11. Compounds of general formula (Ib)
<IMG>
wherein
R2 denotes hydrogen, ethyl, n-propyl, i-propyl,
n-butyl, tert.-butyl, phenyl, benzyl, 2-pyridyl,
3-pyridyl, 4-pyridyl, N-piperidinyl,
N-morpholinyl, N-piperazinyl,
178
4-benzylpiperazinyl, 3-tetrahydrofuranyl, 4-tetrahydropyranyl,
-NMe2, cyclopentyl, cyclohexyl,
adamantan-1-yl, noradamatan-3-yl, norbornan-2-yl
or 5-norbornen-2-yl;
R3 denotes hydrogen;
R4 denotes hydrogen, methyl, ethyl, n-propyl,
i-propyl, n-butyl, tert.-butyl, n-pentyl or
benzyl;
R6 denotes hydrogen, methyl, ethyl, n-propyl,
i-propyl, n-butyl, tert.-butyl, phenyl, benzyl,
cyclopentyl, 2-furyl, 2-pyridylmethyl,
3-pyridylmethyl, 4-pyridylmethyl, cyclohexylmethyl,
2-phenylethyl, N-morpholinomethyl,
N-pyrrolylmethyl, (3-pyridyl)-NH-CH2-,
Ph-COO-CH2-, 3-pyridyl-COO-CH2-, Ph-O-CH2-,
(4-MeO-Ph)-O-CH2-, (4-MeO-Ph)-CH2-O-CH2-,
4-F-Ph-CH2-, 3,4-F-Ph-CH2-, -CH2-OH, -CH2-OMe,
-CH2-OEt, -CH2-NMe2, -COOMe or -COOH,
optionally in the form of the racemates, the
enantiomers, the diastereomers and mixtures
thereof, and optionally the pharmacologically
acceptable acid addition salts thereof.
12. Compounds of general formula (Ia)
<IMG>
wherein
R1 denotes hydrogen;
R2 denotes hydrogen, ethyl, n-propyl, i-propyl,
n-butyl, tert.-butyl, phenyl, benzyl, 2-pyridyl,
179
3-pyridyl, 4-pyridyl, N-piperidinyl,
N-morpholinyl, N-piperazinyl,
4-benzylpiperazinyl, 3-tetrahydrofuranyl, 4-tetrahydropyranyl,
-NMe2, cyclopentyl, cyclohexyl,
adamantan-1-yl, noradamatan-3-yl, norbornan-2-yl
or 5-norbornen-2-yl;
R4 denotes hydrogen, methyl, ethyl, n-propyl,
i-propyl, n-butyl, tert.-butyl, n-pentyl or
benzyl;
R6 denotes hydrogen, methyl, ethyl, n-propyl,
i-propyl, n-butyl, tert.-butyl, phenyl, benzyl,
cyclopentyl, 2-furyl, 2-pyridylmethyl,
3-pyridylmethyl, 4-pyridylmethyl, cyclohexylmethyl,
2-phenylethyl, N-morpholinomethyl,
N-pyrrolylmethyl, (3-pyridyl)-NH-CH2-,
Ph-COO-CH2-, 3-pyridyl-COO-CH2-, Ph-O-CH2-,
(4-MeO-Ph)-O-CH2-, (4-MeO-Ph)-CH2-O-CH2-,
4-F-Ph-CH2-, 3,4-F-Ph-CH2-, -CH2-OH, -CH2-OMe,
-CH2-OEt, -CH2-NMe2, -COOMe or -COOH,
optionally in the form of the racemates, the
enantiomers, the diastereomers and mixtures
thereof, and optionally the pharmacologically
acceptable acid addition salts thereof.
13. Use of a compound according to one of claims 1 to 12
as a pharmaceutical composition.
14. Use of a compound according to one of claims 1 to 12
as a pharmaceutical composition having an
andenosine-antagonistic activity.
15. Pharmaceutical preparations containing as active
substance one or more compounds according to one of claims
1 to 12 or the physiologically acceptable acid addition
salts thereof combined with conventional excipients and/or
carriers.
180
16. Process for preparing triazolopurine derivatives of
general formula (I)
<IMG>
wherein R1, R2, R3, R4, R5 and R6 are defined as in claims 1
to 12, characterised in that
a) a compound of general formula (9)
<IMG>
or a tautomer thereof, wherein R2, R4 and R6 are as
hereinbefore defined, is reacted in a suitable organic
solvent or mixture of solvents under basic conditions with
a suitable alkylating agent of general formula R1-X or
R3-X, wherein R1 and R3 are as hereinbefore defined and X
denotes a leaving group, or
b) a compound of general formula (16)
181
<IMG>
or a tautomer thereof, wherein R2, R5 and R6 are as
hereinbefore defined, is reacted in a suitable organic
solvent or mixture of solvents under basic conditions with
a suitable alkylating agent of general formula R1-X or
R3-X, wherein R1 and R3 are as hereinbefore defined and X
denotes a leaving group, or
c) for R4=R1 a compound of general formula
<IMG>
or a tautomer thereof, wherein R2 and R6 are as
hereinbefore defined, is reacted in a suitable organic
solvent or mixture of solvents under basic conditions with
a suitable alkylating agent of general formula R1-X or
R3-X to form the monoalkylated compounds (9) or directly
to form the dialkylated compounds (I), wherein R1 and R3
are as hereinbefore defined and X denotes a leaving group.
17. Process for preparing triazolopurine derivatives of
general formula (9)
<IMG>
182
or the tautomers thereof, wherein R2, R4 and R6 are defined
as in claims 1 to 12, characterised in that
a) a compound of general formulae
<IMG>
<IMG>
or
wherein R2, R4 and R6 are as hereinbefore defined, is
cyclised under basic, acidic or dehydrating conditions to
obtain the tricyclic triazolopurine derivatives of general
formula (9), or
b) for R2=H, a diamine of general formula
<IMG>
wherein R4 and R6 are as hereinbefore defined, is
converted by thermal reaction with formamide into
triazolopurine derivatives of general formula (9), or
c) for R2=NR8R9, wherein R8 and R9 are as hereinbefore
defined, a nitroso compound of general formula
<IMG>
183
wherein R4 and R6 are as hereinbefore defined, is reacted
under dehydrating conditions with N-formylamines to obtain
triazolopurine derivatives of general formula (9).
18. Process for preparing triazolopurine derivatives of
general formula (16)
<IMG>
or the tautomers thereof, wherein R2, R5 and R6 are defined
as in claims 1 to 12, characterised in that
a) a compound of general formula
<IMG> <IMG>
or
wherein R2, R5 and R6 are as hereinbefore defined, is
cyclised under basic, acidic or dehydrating conditions to
obtain the tricyclic triazolopurine derivatives of general
formula (16), or
b) for R2=H, a diamine of general formula
<IMG>
184
wherein R5 and R6 are as hereinbefore defined, is
converted by thermal reaction with formamide into
triazolopurine derivatives of general formula (16), or
c) for R2=NR8R9 wherein R8 and R9 as hereinbefore defined, a
nitroso compound of general formula
<IMG>
wherein R5 and R6 are as hereinbefore defined, is reacted
with N-formylamines under dehydrating conditions to obtain
triazolopurine derivatives of general formula (16).
