Substituted 2-(chroman-6-yloxyl)-thiazoles and their use as pharmaceuticals

Abstract

The present invention relates to substituted 2-(chroman-6-yloxy)-thiazoles of the formula I, in which Ar, R2, R3 and R4 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 as pharmaceuticals, and pharmaceutical compositions comprising them.

1 - 14 . (canceled) 
     
     
         15 . A method of preparing a compound of formula VI 
       
         
           
           
               
               
           
         
         wherein: 
         Ar is selected from the group consisting of phenyl and a 5-membered or 6-membered monocyclic aromatic heterocycle, which are all unsubstituted or substituted by one or more identical or different substituents R1, wherein the heterocycle comprises 1 or 2 identical or different ring heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and is bonded via a ring carbon atom; 
         R1 is selected from the group consisting of halogen, (C 1 -C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl, (C 3 -C 7 )-cycloalkyl-(C 1 -C 4 )-alkyl-, phenyl, Het1, HO—, (C 1 -C 6 )-alkyl-O—, (C 3 -C 7 )-cycloalkyl-O—, (C 3 -C 7 )-cycloalkyl-(C 1 -C 4 )-alkyl-O—, phenyl-O—, Het1-O— and (C 1 -C 6 )-alkyl-S(O) n —, and two groups R1 bonded to adjacent ring carbon atoms in Ar, together with the carbon atoms carrying them, optionally form a 5-membered to 7-membered mono-unsaturated ring which comprises 0, 1 or 2 identical or different ring heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and which is unsubstituted or substituted by one or more identical or different substituents selected from the group consisting of fluorine and (C 1 -C 4 )-alkyl; 
         R3 is selected from the group consisting of hydrogen, halogen, (C 1 -C 4 )-alkyl and (C 1 -C 4 )-alkyl-O—; 
         R4 is hydrogen or one or more identical or different substituents selected from the group consisting of halogen, (C 1 -C 4 )-alkyl and (C 1 -C 4 )-alkyl-O—; 
         Het1 is a 5-membered or 6-membered monocyclic aromatic heterocycle comprising 1 or 2 identical or different ring heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, which is unsubstituted or substituted by one or more identical or different substituents selected from the group consisting of halogen, (C 1 -C 4 )-alkyl and (C 1 -C 4 )-alkyl-O—; and 
         n is 0, 1 or 2, wherein all numbers n are independent of one another; 
         wherein all phenyl groups, unless specified otherwise, are unsubstituted or substituted by one or more identical or different substituents selected from the group consisting of halogen, (C 1 -C 4 )-alkyl and —O—(C 1 -C 4 )-alkyl; 
         wherein all cycloalkyl groups, independently of any other substituents which can be present on a cycloalkyl group, are optionally substituted by one or more identical substituents selected from the group 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, are optionally substituted by one or more fluorine substituents; 
         said method comprising reacting a compound of formula IVa 
       
       
         
           
           
               
               
           
         
         wherein: 
         Ar, R1, R3, R4, Het1, and n are as defined for the compound of formula VI; and 
         R50 is (C 1 -C 4 )-alkyl; 
         with an acid or a base. 
       
     
     
         16 . The method of  claim 15 , wherein the base is an alkali metal hydroxide. 
     
     
         17 . The method of  claim 16 , wherein the alkali metal hydroxide is lithium hydroxide, sodium hydroxide, or potassium hydroxide. 
     
     
         18 . The method of  claim 17 , wherein the reaction is carried out using an ether as solvent. 
     
     
         19 . The method of  claim 18 , wherein the ether is THF, dioxane, or DME. 
     
     
         20 . The method of  claim 17 , wherein the reaction is carried out using an alcohol as solvent. 
     
     
         21 . The method of  claim 20 , wherein the alcohol is methanol or ethanol. 
     
     
         22 . The method of  claim 15 , wherein the acid is hydrochloric acid or trifluoroacetic acid. 
     
     
         23 . The method of  claim 22 , wherein the reaction is carried out using a chlorinated hydrocarbon, an ether, or an alcohol as solvent. 
     
     
         24 . The method of  claim 23 , wherein the chlorinated hydrocarbon is dichloromethane. 
     
     
         25 . The method of  claim 15 , wherein:
 Ar is selected from the group consisting of phenyl, thiophenyl, pyridinyl and pyrazinyl, which are all unsubstituted or substituted by one or more identical or different substituents R1;   R1 is selected from the group 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—, (C 3 -C 7 )-cycloalkyl-(C 1 -C 4 )-alkyl-O—, and (C 1 -C 6 )-alkyl-S(O) n —;   R3 is selected from the group consisting of hydrogen, halogen, and (C 1 -C 4 )-alkyl;   R4 is hydrogen or one or more identical or different substituents selected from the group consisting of halogen and (C 1 -C 4 )-alkyl;   and   n is 0, 1 or 2, wherein all numbers n are independent of one another;   wherein all cycloalkyl groups, independently of any other substituents which can be present on a cycloalkyl group, are optionally substituted by one or more identical substituents selected from the group 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, are optionally substituted by one or more fluorine substituents.   
     
     
         26 . The method of  claim 15 , wherein:
 Ar is selected from the group consisting of phenyl, thiophenyl, pyridinyl and pyrazinyl, which are all unsubstituted or substituted by one or more identical or different substituents R1;   R1 is selected from the group consisting of halogen, (C 1 -C 6 )-alkyl, HO—, and (C 1 -C 6 )-alkyl-O—;   R3 is selected from the group consisting of hydrogen, halogen, and (C 1 -C 4 )-alkyl; and   R4 is hydrogen or one or more identical or different substituents selected from the group consisting of halogen and (C 1 -C 4 )-alkyl;   wherein all alkyl groups, independently of any other substituents which can be present on an alkyl group, are optionally substituted by one or more fluorine substituents.