Heteroaryl-substituted dicyanopyridines and their use
View Patent ↗The present application relates to novel heteroaryl-substituted dicyanopyridines, 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 cardiovascular disorders.
1. A compound of the formula (I):
wherein
X represents O or S,
R 1 represents phenyl or 5- or 6-membered heteroaryl,
where phenyl and 5- or 6-membered heteroaryl are substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, chlorine, cyano, (C 1 -C 4 )-alkyl, trifluoromethyl, (C 1 -C 4 )-alkoxy, mono-(C 1 -C 4 )-alkylamino, di-(C 1 -C 4 )-alkylamino, hydroxycarbonyl, (C 1 -C 4 )-alkoxycarbonyl, aminocarbonyl, mono-(C 1 -C 4 )-alkylaminocarbonyl, di-(C 1 -C 4 )-alkylaminocarbonyl, pyrrolidino, piperidino, morpholino, piperazino, N′-(C 1 -C 4 )-alkylpiperazino, phenyl and 5- or 6-membered heteroaryl,
where phenyl and 5- or 6-membered heteroaryl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, chlorine, cyano, (C 1 -C 4 )-alkyl, difluoromethyl, trifluoromethyl, (C 1 -C 4 )-alkoxy, difluoromethoxy, trifluoromethoxy, hydroxycarbonyl and (C 1 -C 4 )-alkoxycarbonyl,
R 2 represents hydrogen or methyl,
R 3 represents pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isoxazol-5-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl or imidazol-5-yl, where pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isoxazol-5-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl and imidazol-5-yl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, trifluoromethyl (C 1 -C 6 )-alkyl, (C 1 -C 4 )-alkoxy and —NR A R B , where (C 1 -C 6 )-alkyl and (C 2 -C 4 )-alkoxy may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, trifluoromethyl, hydroxyl, methoxy, ethoxy, hydroxycarbonyl, amino, methylamino, ethylamino, N,N-dimethylamino and N,N-diethylamino, and
where
R A represents hydrogen or (C 1 -C 4 )-alkyl,
where (C 1 -C 4 )-alkyl for its part may be substituted by a substituent selected from the group consisting of hydroxyl and (C 1 -C 4 )-alkoxy,
R B represents hydrogen or (C 1 -C 4 )-alkyl,
where (C 1 -C 4 )-alkyl for its part may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of hydroxyl, (C 1 -C 4 )-alkoxy and hydroxycarbonyl,
R 4 represents hydrogen or methyl,
R 5 represents hydrogen or (C 1 -C 4 )-alkyl,
where (C 1 -C 4 )-alkyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of hydroxyl, methoxy and ethoxy, or
R 4 and R 5 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocycle which may contain a further ring heteroatom from the group consisting of N, O and S and may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of (C 1 -C 4 )-alkyl, hydroxyl, methoxy and ethoxy,
or a salt thereof.
2. The compound of claim 1 , wherein:
X represents S,
R 1 represents phenyl, oxazolyl, thiazolyl or pyridyl,
where phenyl and pyridyl are substututed by a substituent selected from the group consisting of cyano, methoxy, ethoxy, hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methylaminocarbonyl and dimethylaminocarbonyl, and
where phenyl and pyridyl may by substituted by a substituent selected from the group consisting of fluorine, chlorine, methyl, ethyl and trifluoromethyl, and
where oxazolyl and thiazolyl are substituted by a phenyl substituent,
where phenyl may be substituted by a substituent selected from the group consisting of fluorine, chlorine, cyano, methyl, methoxy, hydroxycarbonyl and methoxycarbonyl, and
where oxazolyl and thiazolyl may be substituted by a substituent selected from the group consisting of fluorine, methyl, ethyl, methoxy, hydroxycarbonyl and methoxycarbonyl,
R 2 represents hydrogen,
R 3 represents a group of the formula
where
* denotes the point of attachment to the pyridine, and
where
R 6 represents hydrogen, methyl or ethyl,
R 7 represents hydrogen or (C 1 -C 6 )-alkyl,
where (C 1 -C 6 )-alkyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of hydroxyl and methoxy,
R 8 represents hydrogen or (C 1 -C 6 )-alkyl,
where (C 1 -C 6 )-alkyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of hydroxyl and methoxy,
R 9 represents hydrogen, methyl or ethyl,
R 10 represents hydrogen,
R 11 represents hydrogen or (C 1 -C 6 )-alkyl,
where (C 1 -C 6 )-alkyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of hydroxyl and methoxy,
R 12 represents hydrogen or (C 1 -C 6 )-alkyl,
where (C 1 -C 6 )-alkyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of hydroxyl and methoxy,
R 13 represents hydrogen, methyl or ethyl, and
R 14 represents hydrogen or (C 1 -C 6 )-alkyl,
where (C 1 -C 6 )-alkyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of hydroxyl and methoxy,
R 4 represents hydrogen,
R 5 represents hydrogen, ethyl, n-propyl or sec-butyl,
where ethyl, n-propyl and sec-butyl may be substituted by 1 or 2 hydroxyl substituents, or
R 4 and R 5 together with the nitrogen atom to which they are attached form an azetidinyl or pyrrolidinyl ring which may be substituted by a hydroxyl substituent,
or a salt thereof.
3. A process for preparing compounds of the formula (I) as defined in claim 1 , comprising:
[A] reacting a compound of the formula (II)
in which X, R 3 , R 4 and R 5 have the meanings given in claim 1 , in an inert solvent in the presence of a base with a compound of the formula (III)
in which R 1 and R 2 each have the meanings given in claim 1 and
Q represents a suitable leaving group, preferably halogen, in particular chlorine, bromine or iodine, or represents mesylate, tosylate or triflate, or
[B] if X represents O, a compound of the formula (IV)
in which R 3 , R 4 and R 5 each have the meanings given in claim 1 , in an inert solvent in the presence of a base with a compound of the formula (V)
in which R 1 and R 2 have the meanings given in claim 1 , or
[C] converting a compound of the formula (I-A)
in which R 1 , R 2 and R 3 each have the meanings given in claim 1 , with copper(II) chloride and isoamyl nitrite in a suitable solvent into a compound of the formula (XV)
in which R 1 , R 2 and R 3 each have the meanings given in claim 1 , and reacting the compound of formula (XV) with a compound of the formula (VIII)
in which R 4 and R 5 each have the meanings given in claim 1 , and
in which at least one of the two radicals R 4 and R 5 is different from hydrogen, to give a compound of the formula (I-B)
in which R 1 , R 2 , R 3 , R 4 and R 5 each have the meanings given claim 1 , and
in which at least one of the two radicals R 4 and R 5 is different from hydrogen,
any protective groups present are then removed
and optionally converting the resulting compound of formula (I) with the appropriate (i)
solvent and/or (ii) bases or acid into a salt thereof.
4. A pharmaceutical composition, comprising a compound of claim 1 and an inert nontoxic pharmaceutically suitable auxiliary.
5. The pharmaceutical composition of claim 4 , further comprising one or more further active ingredients selected from the group consisting of lipid metabolism-modifying active ingredients, antidiabetics, antihypertensive drugs and antithrombotic drugs.