Substituted chroman-6-yloxy-cycloalkanes and their use as pharmaceuticals

Abstract

The present invention relates to substituted chroman-6-yloxy-cycloalkanes of the formula (I) in which Ar, R1 to R4, p and q are as defined in the claims. The compounds of the formula (I) are inhibitors of the sodium-calcium exchanger (NCX), especially of the sodium-calcium exchanger of subtype 1 (NCX1), and are suitable for the treatment of diverse disorders in which intracellular calcium homeostasis is disturbed, such as arrhythmias, heart failure and stroke. The invention furthermore relates to processes for the preparation of the compounds of the formula (I), their use in pharmaceuticals, and pharmaceutical compositions comprising them.

1 . A compound of structure (IVb), 
       
         
           
           
               
               
           
         
         in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a pharmaceutically acceptable salt thereof, wherein 
         Ar is phenyl which is unsubstituted or substituted by one or more identical or different substituents R 0 ; 
         R 0  is selected from the series consisting of halogen, (C 1 -C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl, (C 3 -C 7 )-cycloalkyl-(C 1 -C 4 )-alkyl-, HO—, (C 1 -C 6 )-alkyl-O—, (C 3 -C 7 )-cycloalkyl-O— and (C 3 -C 7 )-cycloalkyl-(C 1 -C 4 )-alkyl-O—, and two groups R 0  bonded to adjacent ring carbon atoms in Ar, together with the carbon atoms carrying them, can form a 5-membered to 7-membered mono-unsaturated ring which comprises 0, 1 or 2 identical or different ring heteroatoms selected from the series consisting of nitrogen, oxygen and sulfur, and which is unsubstituted or substituted by one or more identical or different substituents selected from the series consisting of fluorine and (C 1 -C 4 )-alkyl; 
         R 1  is hydrogen or one or more identical or different substituents selected from the series consisting of fluorine and (C 1 -C 4 )-alkyl; 
         R 3  is selected from the series consisting of hydrogen and (C 1 -C 6 )-alkyl, wherein (C 1 -C 6 )-alkyl is unsubstituted or substituted by one or two identical or different substituents selected from the series consisting of (C 3 -C 7 )-cycloalkyl, phenyl, HO— and (C 1 -C 4 )-alkyl-O—; 
         R 4  is hydrogen or one or more identical or different substituents selected from the series consisting of halogen, (C 1 -C 4 )-alkyl and (C 1 -C 4 )-alkyl-O—; 
         wherein all phenyl groups are unsubstituted or substituted by one or more identical or different substituents selected from the series consisting of halogen, (C 1 -C 4 )-alkyl and (C 1 -C 4 )-alkyl-O—, unless specified otherwise; 
         wherein all cycloalkyl bicycloalkyl groups, independently of any other substituents which can be present on a cycloalkyl group can be substituted by one or more identical or different substituents selected from the series consisting of fluorine and (C 1 -C 4 )-alkyl; 
         wherein all alkyl groups, independently of any other substituents which can be present on an alkyl group, can be substituted by one or more fluorine substituents. 
       
     
     
         2 . A compound of the formula (IVb) according to  claim 1  in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a pharmaceutically acceptable salt thereof, wherein
 Ar is phenyl which is unsubstituted or substituted by one or more identical or different substituents R 0 ; 
 R 0  is selected from the series consisting of halogen, (C 1 -C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl, (C 3 -C 7 )-cycloalkyl-(C 1 -C 4 )-alkyl-, HO—, (C 1 -C 6 )-alkyl-O—, (C 3 -C 7 )-cycloalkyl-O— and (C 3 -C 7 )-cycloalkyl-(C 1 -C 4 )-alkyl-O; 
 R 1  is hydrogen or one or more identical or different substituents selected from the series consisting of fluorine and (C 1 -C 4 )-alkyl; 
 R 3  is selected from the series consisting of hydrogen and (C 1 -C 6 )-alkyl, wherein (C 1 -C 6 )-alkyl is unsubstituted or substituted by one or two identical or different substituents selected from the series consisting of (C 3 -C 7 )-cycloalkyl and phenyl; 
 R 4  is hydrogen or one or more identical or different substituents selected from the series consisting of halogen, (C 1 -C 4 )-alkyl and (C 1 -C 4 )-alkyl-O—; 
 wherein all phenyl groups are unsubstituted or substituted by one or more identical or different substituents selected from the series consisting of halogen, (C 1 -C 4 )-alkyl and (C 1 -C 4 )-alkyl-O—, unless specified otherwise; 
 wherein all cycloalkyl groups, independently of any other substituents which can be present on a cycloalkyl group, can be substituted by one or more identical or different substituents selected from the series consisting of fluorine and (C 1 -C 4 )-alkyl; 
 wherein all alkyl groups, independently of any other substituents which can be present on an alkyl group, can be substituted by one or more fluorine substituents. 
 
     
     
         3 . A compound of the formula (IVb) according to  claim 1  in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a pharmaceutically acceptable salt thereof, wherein
 Ar is phenyl which is unsubstituted or substituted by one or more identical or different substituents R 0 ; 
 R 0  is selected from the series consisting of halogen, (C 1 -C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl, (C 3 -C 7 )-cycloalkyl-(C 1 -C 4 )-alkyl-, HO—, (C 1 -C 6 )-alkyl-O—, (C 3 -C 7 )-cycloalkyl-O— and (C 3 -C 7 )-cycloalkyl-(C 1 -C 4 )-alkyl-O—; 
 R 1  is hydrogen or one or more identical or different substituents selected from the series consisting of fluorine and (C 1 -C 4 )-alkyl; 
 R 3  is selected from the series consisting of hydrogen and (C 1 -C 6 )-alkyl, wherein (C 1 -C 6 )-alkyl is unsubstituted or substituted by one or two identical or different substituents selected from the series consisting of (C 3 -C 7 )-cycloalkyl and phenyl; 
 R 4  is hydrogen or one or more identical or different substituents selected from the series consisting of halogen, (C 1 -C 4 )-alkyl and (C 1 -C 4 )-alkyl-O—; 
 wherein all phenyl groups are unsubstituted or substituted by one or more identical or different substituents selected from the series consisting of halogen, (C 1 -C 4 )-alkyl and (C 1 -C 4 )-alkyl-O—, unless specified otherwise; 
 wherein all cycloalkyl groups, independently of any other substituents which can be present on a cycloalkyl group, can be substituted by one or more identical or different substituents selected from the series consisting of fluorine and (C 1 -C 4 )-alkyl; 
 wherein all alkyl groups, independently of any other substituents which can be present on an alkyl group, can be substituted by one or more fluorine substituents. 
 
     
     
         4 . A compound of the formula (IVb) according to  claim 1  in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a pharmaceutically acceptable salt thereof, wherein
 Ar is phenyl which is unsubstituted or substituted by one or more identical or different substituents R 0 ; 
 R 0  is selected from the series consisting of halogen, (C 1 -C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl, (C 1 -C 6 )-alkyl-O— and (C 3 -C 7 )-cycloalkyl-O—; 
 R 1  is hydrogen or one or more identical or different substituents selected from the series consisting of fluorine and (C 1 -C 4 )-alkyl; 
 R 3  is hydrogen; 
 R 4  is hydrogen or one or more identical or different substituents selected from the series consisting of halogen and (C 1 -C 4 )-alkyl; 
 wherein all cycloalkyl groups, independently of any other substituents which can be present on a cycloalkyl group, can be substituted by one or more identical or different substituents selected from the series consisting of fluorine and (C 1 -C 4 )-alkyl; 
 wherein all alkyl groups, independently of any other substituents which can be present on an alkyl group, can be substituted by one or more fluorine substituents.