Substituted bipyridine derivatives and their use as adenosine receptor ligands
View Patent ↗The present invention relates to novel substituted 2,4′- and 3,4′-bipyridine derivatives, to processes for their preparation, to their use for the treatment and/or prophylaxis of diseases and to their use for preparing medicaments for the treatment and/or prophylaxis of diseases, preferably for the treatment and/or prevention of hypertension and other cardiovascular disorders.
1. Compound of the formula (I)
in which
X represents N and Y represents C—R 6 , where
R 6 represents hydrogen or (C 1 -C 4 )-alkyl,
Z represents N—R 7 or O, where
R 7 represents hydrogen or (C 1 -C 4 )-alkyl which may be substituted by hydroxyl or (C 1 -C 4 )-alkoxy,
R 1 and R 2 are identical or different and independently of one another represent hydrogen or (C 1 -C 6 )-alkyl which may be mono- or disubstituted by identical or different substituents from a group consisting of hydroxyl, (C 1 -C 4 )-alkoxy, amino, mono-(C 1 -C 4 )-alkylamino, di-(C 1 -C 4 )-alkylamino, carboxyl, and (C 1 -C 4 )-alkoxycarbonyl,
R 3 represents hydrogen or (C 1 -C 6 )-alkyl which may be mono- or disubstituted by identical or different substituents from the group consisting of (C 3 -C 6 )-cycloalkyl, oxo, hydroxyl, (C 1 -C 4 )-alkoxy, carboxyl, amino, mono-(C 1 -C 4 )-alkylamino and di-(C 1 -C 4 )-alkylamino, or represents (C 4 -C 6 )-cycloalkyl,
where the cycloalkyl radicals mentioned for their part may be substituted up to two times by identical or different substituents from the group consisting of (C 1 -C 4 )-alkyl, hydroxyl, oxo and (C 1 -C 4 )-alkoxy,
R 4 represents hydrogen, halogen, (C 1 -C 4 )-alkyl or (C 1 -C 4 )-alkoxy, where alkyl and alkoxy may each be substituted up to three times by fluorine,
and
R 5 represents (C 6 -C 10 )-aryl, which may
(i) be mono- or disubstituted by identical or different substituents from the group consisting of halogen, nitro, cyano, (C 1 -C 6 )-alkyl, phenyl, hydroxyl, (C 1 -C 6 )-alkoxy, amino, mono-(C 1 -C 6 )-alkylamino, mono-(C 2 -C 6 )-alkenylamino and di-(C 1 -C 6 )-alkylamino
and/or
(ii) be substituted by a group of the formula -L-R 8 , where
L represents a bond, NH or O
and
R 8 represents phenyl, which may be mono- to trisubstituted by identical or different substituents from the group consisting of halogen, nitro, cyano, (C 1 -C 6 )-alkyl, trifluoromethyl, hydroxyl, (C 1 -C 6 )-alkoxy, difluoromethoxy, trifluoromethoxy, amino, mono-(C 1 -C 6 )-alkylamino, di-(C 1 -C 6 )-alkylamino, (C 1 -C 6 )-alkoxycarbonyl and carboxyl,
or a salt thereof.
2. The compound of claim 1 in which
X represents N and Y represents CH,
Z represents N—R 7 or O, where
R 7 represents hydrogen or methyl,
R 1 represents hydrogen or (C 1 -C 4 )-alkyl which may be substituted by hydroxyl, (C 1 -C 4 )-alkoxy, amino, mono-(C 1 -C 4 )-alkylamino, di-(C 1 -C 4 )-alkylamino, carboxyl, or (C 1 -C 4 )-alkoxycarbonyl,
R 2 represents hydrogen or methyl,
R 3 represents (C 1 -C 4 )-alkyl which may be mono- or disubstituted by identical or different substituents from the group consisting of (C 3 -C 5 )-cycloalkyl, oxo, hydroxyl, (C 1 -C 3 )-alkoxy, amino, mono-(C 1 -C 3 )-alkylamino and di-(C 1 -C 3 )-alkylamino, or represents cyclopentyl or cyclohexyl,
where the (C 3 -C 5 )-cycloalkyl, cyclopentyl and cyclohexyl radicals mentioned for their part may be substituted up to two times by identical or different substituents from the group consisting of hydroxyl and methoxy,
R 4 represents hydrogen, fluorine or chlorine,
and
R 5 represents phenyl which may
(i) be mono- or disubstituted by identical or different substituents from the group consisting of fluorine, chlorine, cyano, (C 1 -C 4 )-alkyl, amino, mono-(C 1 -C 4 )-alkylamino and di-(C 1 -C 4 )-alkylamino
and/or
(ii) be substituted by a group of the formula -L-R 8 , where
L represents a bond or NH
and
R 8 represents phenyl which may be mono- to trisubstituted by identical or different substituents from the group consisting of fluorine, chlorine, cyano, (C 1 -C 4 )-alkyl, trifluoromethyl, (C 1 -C 4 )-alkoxy, trifluoromethoxy and carboxyl,
or a salt thereof.
3. The compound of claim 1 in which
X represents N and Y represents CH,
Z represents NH or O,
R 1 represents hydrogen or (C 1 -C 4 )-alkyl which may be substituted by hydroxyl, (C 1 -C 4 )-alkoxy, amino, mono-(C 1 -C 4 )-alkylamino or di-(C 1 -C 4 )-alkylamino,
R 2 represents hydrogen or methyl,
R 3 represents (C 1 -C 4 )-alkyl which may be mono- or disubstituted by identical or different substituents from the group consisting of oxo, hydroxyl, methoxy, ethoxy and amino,
R 4 represents hydrogen,
and
R 5 represents phenyl which may
(i) be mono- or disubstituted by identical or different substituents from the group consisting of fluorine, chlorine, cyano, (C 1 -C 4 )-alkyl and amino
and/or
(ii) be substituted by a group of the formula -L-R 8 , where
L represents a bond or NH
and
R 8 represents phenyl which may be mono- or disubstituted by identical or different substituents from the group consisting of fluorine, chlorine, cyano, methyl, trifluoromethyl and methoxy,
or a salt thereof.
4. A process for preparing a compound of formula (I) as defined in claim 1 , comprising
reacting a compound of the formula (II)
in which R 1 , R 2 , R 3 , R 4 , X, Y and Z are each as defined in claim 1
in an inert solvent in the presence of a base with a compound of the formula (III)
in which R 5 is as defined in claim 1 and
Q represents a suitable leaving group,
and optionally reacting the resulting compounds of formula (I) with a base or acid thereby producing a salt thereof.
5. A pharmaceutical composition comprising a compound of claim 1 and an inert non-toxic pharmaceutically suitable auxiliary.