Substituted heterocycles, their use as medicament, and pharmaceutical preparations comprising them
View Patent ↗The invention relates to compounds of formula I in which A, R1, R2, R3, R4, R5, R6, R7 and n have the meanings stated in the claims. The compounds are particularly suitable as antiarrhythmic active ingredients, in particular for the treatment and prophylaxis of atrial arrhythmias, for example atrial fibrillation (AF) or atrial flutter.
1. A compound of formula I,
in which:
A is C, S or S═O;
n is 0, 1, 2 or 3;
R1 is phenyl, pyridyl, thienyl, naphthyl, quinolinyl, pyrimidinyl or pyrazinyl,
where each of these aryl radicals is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CN, alkoxy having 1, 2, 3 or 4 C atoms, OCF 3 , methylsulfonyl, CF 3 , alkyl having 1, 2, 3 or 4 C atoms, dimethylamino, sulfamoyl, acetyl, and methylsulfonylamino;
or
R1 is cycloalkyl having 3, 4, 5, 6 or 7 C atoms;
R2 is phenyl, pyridyl, thienyl, naphthyl, quinolinyl, pyrimidinyl or pyrazinyl,
where each of these aryl radicals is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CN, COOMe, CONH 2 , alkoxy having 1, 2, 3 or 4 C atoms, OCF 3 , OH, methylsulfonyl, CF 3 , alkyl having 1, 2, 3 or 4 C atoms, dimethylamino, sulfamoyl, acetyl, and methylsulfonylamino;
R3 is C p H 2p —R8;
p is 0, 1, 2, 3, 4 or 5;
R8 is CH 3 , CH 2 F, CHF 2 , CF 3 , cycloalkyl having 3, 4, 5, 6 or 7 C atoms, C≡CH, C≡C—CH 3 , alkoxy having 1, 2, 3 or 4 C atoms, phenyl or pyridyl,
where phenyl and pyridyl are unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF 3 , OCF 3 , CN, COOMe, CONH 2 , COMe, OH, alkyl having 1, 2, 3 or 4 C atoms, alkoxy having 1, 2, 3 or 4 C atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
R4 is hydrogen or alkyl having 1, 2 or 3 C atoms;
R5 is hydrogen or alkyl having 1, 2 or 3 C atoms;
R6 and R7
are independently of one another hydrogen, F or alkyl having 1, 2, or 3 C atoms;
and the pharmaceutically acceptable salts and trifluoroacetates thereof.
2. A compound of formula I as claimed in claim 1 , in which:
A is C, S or S═O;
n is 0, 1, 2 or 3;
R1 is phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thienyl, 3-thienyl, 1-naphthyl, 2-naphthyl, 2-quinolinyl, 3-quinolinyl, 4-quinolinyl, 5-quinolinyl, 6-quinolinyl, 7-quinolinyl, 8-quinolinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, 3-pyridazinyl or 4-pyridazinyl,
where each of these aryl radicals is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CN, alkoxy having 1, 2, 3 or 4 C atoms, OCF 3 , methylsulfonyl, CF 3 , alkyl having 1, 2, 3 or 4 C atoms, dimethylamino, sulfamoyl, acetyl, and methylsulfonylamino;
or
R1 is cyclohexyl;
R2 is phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thienyl, 3-thienyl, 1-naphthyl, 2-naphthyl, 2-quinolinyl, 3-quinolinyl, 4-quinolinyl, 5-quinolinyl, 6-quinolinyl, 7-quinolinyl, 8-quinolinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, 3-pyridazinyl or 4-pyridazinyl,
where each of these aryl radicals is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CN, COOMe, CONH 2 , alkoxy having 1, 2, 3 or 4 C atoms, OCF 3 , OH, methylsulfonyl, CF 3 , alkyl having 1, 2, 3 or 4 C atoms, dimethylamino, sulfamoyl, acetyl, and methylsulfonylamino;
R3 is C p H 2p —R8;
p is 0, 1, 2, 3, 4 or 5;
R8 is CH 3 , CH 2 F, CHF 2 , CF 3 , cycloalkyl having 3, 4, 5, 6 or 7 C atoms, C≡CH, C≡C—CH 3 , alkoxy having 1, 2, 3 or 4 C atoms, phenyl or 2-pyridyl,
where phenyl and 2-pyridyl are unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF 3 , OCF 3 , CN, COOMe, CONH 2 , COMe, OH, alkyl having 1, 2, 3 or 4 C atoms, alkoxy having 1, 2, 3 or 4 C atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
R4 is hydrogen or alkyl having 1, 2 or 3 C atoms;
R5 is hydrogen or alkyl having 1, 2 or 3 C atoms;
R6 and R7
are independently of one another hydrogen, F or alkyl having 1, 2, or 3 C atoms;
and the pharmaceutically acceptable salts and trifluoroacetates thereof.
3. A compound of formula I as claimed in claim 1 , in which:
A is C or S═O;
n is 0, 1, 2 or 3;
R1 is phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thienyl, 3-thienyl, 1-naphthyl, 2-naphthyl, 2-quinolinyl, 3-quinolinyl, 4-quinolinyl, 5-quinolinyl, 6-quinolinyl, 7-quinolinyl or 8-quinolinyl,
where each of these aryl radicals is unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CN, alkoxy having 1, 2, 3 or 4 C atoms, OCF 3 , methylsulfonyl, CF 3 and alkyl having 1, 2, 3 or 4 C atoms;
or
R1 is cyclohexyl;
R2 is phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thienyl, 3-thienyl, 1-naphthyl, 2-naphthyl, 2-quinolinyl, 3-quinolinyl, 4-quinolinyl, 5-quinolinyl, 6-quinolinyl, 7-quinolinyl or 8-quinolinyl,
where each of these aryl radicals is unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of Cl, Br, I, CN, CF 3 , alkyl having 1, 2, 3 or 4 C atoms;
R3 is C p H 2p —R8;
p is 0, 1, 2, 3 or 4;
R8 is CH 3 , CH 2 F, CHF 2 , CF 3 , cycloalkyl having 3, 4, 5 or 6 C atoms, C≡CH, C≡C—CH 3 , alkoxy having 1, 2, 3 or 4 C atoms, phenyl or 2-pyridyl,
where phenyl and 2-pyridyl are unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF 3 , OCF 3 , CN, COOMe, CONH 2 , COMe, OH, alkyl having 1, 2, 3 or 4 C atoms and alkoxy having 1, 2, 3 or 4 C atoms;
R4 is hydrogen or alkyl having 1, 2 or 3 C atoms;
R5 is hydrogen or alkyl having 1, 2 or 3 C atoms;
R6 and R7
are independently of one another hydrogen, F or alkyl having 1, 2, or 3 C atoms;
and the pharmaceutically acceptable salts and trifluoroacetates thereof.
4. A pharmaceutical composition comprising a pharmaceutically effective amount of at least one compound of formula I as claimed in claim 1 or a pharmaceutically acceptable salt thereof as active ingredient, together with one or more pharmaceutically acceptable carriers or additives.
5. A pharmaceutical composition comprising an effective amount of at least one compound of formula I as claimed in claim 1 or a pharmaceutically acceptable salt thereof as active ingredient, together with one or more pharmaceutically acceptable carriers or additives, and in combination with one or more other pharmacologically active ingredients or pharmaceuticals.
6. A pharmaceutical composition comprising a pharmaceutically effective amount of at least one compound of formula I as claimed in claim 1 , or a pharmaceutically acceptable salt thereof, and a beta blocker as active ingredients, together with one or more pharmaceutically acceptable carriers or additives.
7. A pharmaceutical composition comprising a pharmaceutically effective amount of at least one compound of formula I as claimed in claim 1 , or a pharmaceutically acceptable salt thereof, and an IKs channel blocker as active ingredients, together with one or more pharmaceutically acceptable carriers or additives.