2-alkoxy-substituted dicyanopyridines and their use
The present application relates to novel 2-alkoxy-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)
in which
X represents O or S,
R 1 represents thiazolyl,
where the thiazolyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of halogen, nitro, cyano, (C 1 -C 6 )-alkyl, trifluoromethyl, hydroxyl, (C 1 -C 6 )-alkoxy, amino, mono-(C 1 -C 6 )-alkylamino, di-(C 1 -C 6 )-alkylamino, hydroxycarbonyl, (C 1 -C 6 )-alkoxycarbonyl, aminocarbonyl, mono-(C 1 -C 6 )-alkylaminocarbonyl, di-(C 1 -C 6 )-alkylamino-carbonyl, (C 3 -C 7 )-cycloalkylaminocarbonyl, aminosulphonyl, mono-(C 1 -C 6 )-alkylaminosulphonyl, di-(C 1 -C 6 )-alkylaminosulphonyl, (C 1 -C 6 )-alkylsulphonylamino, and -L-R 5 ,
in which
L represents a bond, NH or O,
R 5 represents phenyl,
where phenyl may be substituted by 1 to 3 substituents independently of one another selected 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, hydroxycarbonyl and (C 1 -C 6 )-alkoxycarbonyl,
R 2 represents hydrogen or (C 1 -C 4 )-alkyl,
R 3 represents phenyl,
where phenyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of halogen, cyano, hydroxyl, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkoxy, (C 3 -C 7 )-cycloalkoxy, and —NR A R B ,
where (C 1 -C 6 )-alkyl and (C 1 -C 6 )-alkoxy may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of fluorine, trifluoromethyl, (C 3 -C 7 )-cycloalkyl, hydroxyl, (C 1 -C 4 )-alkoxy, hydroxycarbonyl, (C 1 -C 4 )-alkoxycarbonyl, amino, aminocarbonyl, mono-(C 1 -C 4 )-alkylamino and di-(C 1 -C 4 )-alkylamino,
and
where (C 3 -C 7 )-cycloalkoxy may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of (C 1 -C 4 )-alkyl, hydroxyl, oxo and (C 1 -C 4 )-alkoxy,
and
in which
R A represents hydrogen or (C 1 -C 6 )-alkyl,
where (C 1 -C 6 )-alkyl for its part may be substituted by 1 to 3 fluorine substituents,
and
where (C 1 -C 6 )-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, (C 1 -C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl, (C 1 -C 6 )-alkylcarbonyl, (C 1 -C 4 )-alkylsulphonyl or (C 3 -C 7 )-cycloalkyl-sulphonyl,
where (C 1 -C 6 )-alkyl for its part may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, trifluoromethyl, (C 3 -C 7 )-cycloalkyl, hydroxyl, (C 1 -C 4 )-alkoxy, hydroxycarbonyl, (C 1 -C 4 )-alkoxycarbonyl, amino, mono-(C 1 -C 4 )-alkylamino and di-(C 1 -C 4 )-alkylamino,
and
where (C 3 -C 7 )-cycloalkyl for its part may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of (C 1 -C 4 )-alkyl, hydroxyl, oxo and (C 1 -C 4 )-alkoxy,
R 4 represents (C 1 -C 6 )-alkyl or (C 3 -C 7 )-cycloalkyl,
where (C 1 -C 6 )-alkyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, trifluoromethyl, (C 3 -C 7 )-cycloalkyl, hydroxyl, (C 1 -C 4 )-alkoxy, hydroxycarbonyl, (C 1 -C 4 )-alkoxycarbonyl, amino, mono-(C 1 -C 4 )-alkylamino, di-(C 1 -C 4 )-alkylamino, aminocarbonyl, mono-(C 1 -C 4 )-alkylaminocarbonyl, and di-(C 1 -C 4 )-alkylaminocarbonyl,
where (C 1 -C 4 )-alkoxy may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of hydroxyl and (C 1 -C 4 )-alkoxy
and
where (C 3 -C 7 )-cycloalkyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of (C 1 -C 4 )-alkyl, hydroxyl, (C 1 -C 4 )-alkoxy, hydroxycarbonyl, (C 1 -C 4 )-alkoxycarbonyl, amino, mono-(C 1 -C 4 )-alkylamino and di-(C 1 -C 4 )-alkylamino,
or a salt thereof.
2. The compound of claim 1 in which
X represents S,
R 1 represents thiazolyl,
where thiazolyl 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, trifluoromethyl, (C 1 -C 4 )-alkoxy, amino, mono-(C 1 -C 4 )-alkylamino, di-(C1-C 4 )-alkylamino, hydroxycarbonyl, (C 1 -C 4 )-alkoxycarbonyl, aminocarbonyl, mono-(C 1 -C 4 )-alkylaminocarbonyl, di-(C 1 -C 4 )-alkylaminocarbonyl, (C 3 -C 6 )-cycloalkylaminocarbonyl, (C 1 -C 4 )-alkylsulphonylamino, and -L-R 5 ,
in which
L represents a bond or NH,
R 5 represents phenyl,
where phenyl 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, trifluoromethyl, (Ct -C 4 )-alkoxy, trifluoromethoxy, amino, hydroxycarbonyl and (C 1 -C 4 )-alkoxycarbonyl,
R 2 represents hydrogen or methyl,
R 3 represents phenyl,
where phenyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, (C 1 -C 6 )-alkyl, hydroxyl, (C 1 -C 4 )-alkoxy and —NR A R B ,
where (C 1 -C 6 )-alkyl and (C 1 -C 4 )-alkoxy may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of fluorine, trifluoromethyl, hydroxyl, methoxy, ethoxy, hydroxycarbonyl, amino, methylamino, ethylamino, NN-dimethylamino and N,N-diethylamino,
and
in which
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 (C 1 -C 6 )-alky or (C 4 -C 6 )-cycloalkyl,
where (C 1 -C 6 )-alkyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, trifluoromethyl, (C 3 -C 7 )-cycloalkyl, hydroxyl, methoxy, ethoxy, hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl, amino, methylamino, ethylamino, N,N-dimethylamino, and N,N-diethylamino
and
where (C 3 -C 7 )-cycloalkyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of methyl, hydroxyl, methoxy, hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl, amino, methylamino and N,N-dimethylamino,
or a salt thereof.
3. The compound of claim 1 in which
X represents O or S,
R 1 represents thiazolyl
where thiazolyl is substituted by a -L-R 5 substituent,
in which
L represents a bond or NH,
R 5 represents phenyl,
where phenyl for its part may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, chlorine, methyl, methoxy, ethoxy, hydroxycarbonyl, methoxycarbonyl and ethoxycarbonyl,
and
where thiazolyl may be substituted by a substituent selected from the group consisting of fluorine, methyl, ethyl, methoxy, hydroxycarbonyl and methoxycarbonyl,
R 2 represents hydrogen or methyl,
R 3 represents phenyl
where phenyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, (C 1 -C 6 )-alkyl, hydroxyl, (C 1 -C 4 )-alkoxy and —NR A R B ,
where (C 1 -C 6 )-alkyl and (C 1 -C 4 )-alkoxy may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of fluorine, trifluoromethyl, hydroxyl, methoxy, ethoxy, hydroxycarbonyl-yl, amino, methylamino, ethylamino, NN-dimethylamino and N,N-diethylamino,
and
in which
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 (C 1 -C 6 )-alkyl or (C 4 -C 6 )-cycloalkyl,
where (C 1 -C 6 )-alkyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, trifluoromethyl, (C 3 -C 7 )-cycloalkyl, hydroxyl, methoxy and ethoxy,
and
where (C 4 -C 6 )-cycloalkyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of methyl, hydroxyl and methoxy,
or a salt thereof.
4. The compound of claim 1 in which
X represents S,
R 1 represents thiazolyl,
where thiazolyl is substituted by a -L-R 5 substituent,
in which
L represents a bond or NH,
R 5 represents phenyl,
where phenyl for its part may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, chlorine, methyl, methoxy, ethoxy, hydroxycarbonyl, methoxycarbonyl and ethoxycarbonyl,
and
where 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 phenyl,
where phenyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of (C 1 -C 6 )-alkyl, hydroxyl and (C 1 -C 4 )-alkoxy,
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 hydroxyl and methoxy, and
R 4 represents (C 1 -C 4 )-alkyl,
where alkyl may be substituted by 1 or 2 hydroxyl substituents,
or a salt thereof.
5. A process for preparing a compound of the formula (I) as defined in claim 1 , comprising:
[A] reacting a compound of the formula (II-A)
in which X, R 1 , R 2 and R 3 each have the meanings given in claim 1 ,
in an inert solvent in the presence of a suitable base with a compound of the formula (IV)
R 4 —OH (IV),
in which R 4 has the meaning given in claim 1 , to produce a compound of the formula (III-A)
or
[B] in the case that X represents S, reacting a compound of the formula (II-B)
in which R 3 and R 4 each have the meanings given in claim 1
in an inert solvent with an alkali metal sulphide to produce a compound of the formula (III-B)
reacting the compound of formula (III-B) in an inert solvent in the presence of a base with a compound of the formula (V)
in which R 1 and R 2 each have the meanings given in claim 1 and
Q represents a leaving group,
and removing any protective groups present to provide the compound of formula (I), which is optionally converted with a (i) solvent and/or (ii) base or acid into a salt thereof.
6. A pharmaceutical composition comprising the compound of claim 1 and an inert nontoxic pharmaceutically suitable auxiliary.
7. The method of claim 5 , wherein the reaction step wherein the compound of formula (II-A) is converted into the compound of formula (III-A) includes copper(II) chloride and isoamyl nitrite in a suitable solvent.
8. The method of claim 5 , wherein Q represents halogen, mesylate, tosylate or triflate.
9. The compound of claim 1 , wherein the compound is 2-({[2-(4-Chlorophenyl)-1,3-thiazol-4-yl]methyl}sulphanyl)-4-[4-(2-hydroxyethoxy)phenyl]-6-methoxypyridine-3,5-dicarbonitrile, having the formula