NOVEL SUBSTITUTED BIPYRIDINE DERIVATIVES AND THEIR USE AS ADENOSINE RECEPTOR LIGANDS
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 . A compound of formula (I)
wherein
one of the two ring members X and Y represents N and the other 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, (C 1 -C 4 )-alkoxycarbonyl and a 4- to 7-membered heterocycle,
where the heterocycle mentioned contains one or two ring heteroatoms from the group consisting of N, O and S and for its part may be mono- or disubstituted by identical or different substituents from the group consisting of (C 1 -C 4 )-alkyl, hydroxyl, oxo and (C 1 -C 4 )-alkoxy,
or
R 1 and R 2 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle which may contain a further ring heteroatom from the group consisting of N, O and S and which may be mono- or disubstituted by identical or different substituents from the group consisting of (C 1 -C 4 )-alkyl, hydroxyl, oxo and (C 1 -C 4 )-alkoxy,
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 and where in these cycloalkyl radicals a ring CH 2 -group may be replaced by an oxygen atom,
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 5 to 10-membered heteroaryl having up to three ring heteroatoms from the group consisting of N, O and S, which may in each case
(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 pyrrolidino, piperidino, morpholino, piperazino, N′—(C 1 -C 4 )-alkylpiperazino or a group of the formula -L-R 8 , where
L represents a bond, NH or O
and
R 8 represents phenyl or 5- or 6-membered heteroaryl having up to three ring heteroatoms from the group consisting of N, O and S, each of 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 wherein
one of the two ring members X and Y represents N and the other 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, (C 1 -C 4 )-alkoxycarbonyl or a 5- or 6-membered heterocycle,
where the heterocycle mentioned contains one or two ring heteroatoms from the group consisting of N and O and for its part may be mono- or disubstituted by identical or different substituents from the group consisting of methyl, ethyl, hydroxyl, methoxy and ethoxy,
R 2 represents hydrogen or methyl
or
R 1 and R 2 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocycle which may contain a further ring heteroatom from the group consisting of N and O and which may be mono- or disubstituted by identical or different substituents from the group consisting of methyl, ethyl, hydroxyl, methoxy and ethoxy,
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 and in cyclopentyl and cyclohexyl a ring CH 2 -group may be replaced by an oxygen atom,
R 4 represents hydrogen, fluorine or chlorine,
and
R 5 represents 5- or 6-membered heteroaryl having up to three ring heteroatoms from the group consisting of N, O and S, which may in each case
(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 morpholino, N′—(C 1 -C 4 )-alkylpiperazino or a group of the formula -L-R 8 , where
L represents a bond or NH
and
R 8 represents phenyl or 5- or 6-membered heteroaryl having up to three ring heteroatoms from the group consisting of N, O and S, each of 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 wherein
one of the two ring members X and Y represents N and the other 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
or
R 1 and R 2 together with the nitrogen atom to which they are attached form a pyrrolidino, piperidino, morpholino or piperazino ring, each of which may be mono- or disubstituted by identical or different substituents from the group consisting of methyl, ethyl, hydroxyl, methoxy and ethoxy,
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 5- or 6-membered heteroaryl having up to two ring heteroatoms from the group consisting of N, O and S which may in each case
(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 or pyridyl, each of 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 . The compound of claim 1 wherein
X represents N,
Y represents CH,
Z represents 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
or
R 1 and R 2 together with the nitrogen atom to which they are attached form a pyrrolidino, piperidino, morpholino, piperazino or N′-methylpiperazino ring,
R 3 represents 2-hydroxyethyl, 2-hydroxy-1-methylethyl, 2-hydroxypropyl, 2-hydroxy-2-methylpropyl, 3-hydroxypropyl or 2,3-dihydroxypropyl,
R 4 represents hydrogen,
and
R 5 represents pyrazolyl, oxazolyl, thiazolyl, pyridyl or pyrimidinyl which may in each case
(i) be substituted by methyl, ethyl or amino
and
(ii) be substituted by a group of the formula -L-R 8 , where
L represents a bond or NH
and
R 8 represents phenyl or pyridyl, each of which may be mono- or disubstituted by identical or different substituents from the group consisting of fluorine, chlorine, cyano, methyl and methoxy,
or a salt thereof.
5 . A compound of claim 1 , wherein
one of the two ring members X and Y represents N and the other represents CH,
Z represents NH or O,
R 1 and R 2 each represent hydrogen,
R 3 represents 2-hydroxyethyl, 2-hydroxy-1-methylethyl, 2-hydroxypropyl, 2-hydroxy-2-methylpropyl, 3-hydroxypropyl, 2,3-dihydroxypropyl or acetyl,
R 4 represents hydrogen,
and
R 5 represents oxazolyl, thiazolyl or pyridyl, each of which may be substituted by methyl, ethyl, amino or a group of the formula -L-R 8 , where
L represents a bond or NH
and
R 8 represents phenyl or pyridyl, each of which may be mono- or disubstituted by identical or different substituents from the group consisting of fluorine, chlorine, cyano, methyl and methoxy,
or a salt thereof.
6 . A process for preparing a compound of the formula (I) as defined in claim 1 , comprising
reacting a compound of 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 formula (III)
in which R 5 is as defined in claim 1 and
Q represents a suitable leaving group, such as halogen, mesylate, tosylate or triflate, and optionally converting the resulting compounds of formula (I) using the appropriate (i) solvent and/or (ii) base or acid into a salt thereof.
7 . (canceled)
8 . (canceled)
9 . (canceled)
10 . A pharmaceutical composition, comprising a compound of claim 1 and an inert non-toxic pharmaceutically suitable auxiliary.
11 . The pharmaceutical composition of claim 10 , further comprising an active compounds selected from the group consisting of a lipid metabolism-modifying active compound, an antidiabetic, a hypotensive active compound and an antithrombotic active compound.
12 . (canceled)
13 . (canceled)
14 . A method of treatment and/or prophylaxis of hypertension, coronary heart disease, acute coronary syndrome, angina pectoris, heart failure, myocardial infarction and atrial fibrillation comprising administering an effective amount of at least one compound claim 1 to a human or animal in need thereof.
15 . A method for the treatment and/or prophylaxis of diabetes, metabolic syndrome and dyslipidaemia comprising administering an effective amount of at least one compound of claim 1 to a human or animal in need thereof.
16 . A method of treatment and/or prophylaxis of hypertension, coronary heart disease, acute coronary syndrome, angina pectoris, heart failure, myocardial infarction and atrial fibrillation comprising administering an effective amount of the pharmaceutical composition of claim 10 to a human or animal in need thereof.
17 . A method of treatment and/or prophylaxis of diabetes, metabolic syndrome and dyslipidaemia comprising administering an effective amount of the pharmaceutical composition of claim 10 to a human or animal in need thereof.