New oxabispidine compunds useful in the treatment of cardiac arrhythmias

Abstract

There is provided compounds of formula I, wherein R 1 , R 2 , R 3 , R 4 , R 41 to R 46 , A, B and G have meanings given in the description, which are useful in the prophylaxis and in the treatment of arrhythmias, in particular atrial and ventricular arrhythmias.

1 - 45 . (canceled) 
   
   
       46 . A compound of formula II, 
     
       
         
         
             
             
         
       
       wherein: 
       R 2  represents H, halo, C 1-6  alkyl, —OR 13 , -E-N(R 14 )R 15  or, together with R 3 , represents ═O; 
       R 3  represents H, C 1-6  alkyl or, together with R 2 , represents ═O; 
       R 13  represents H, C 1-6  alkyl, -E-aryl, -E-Het 6 , —C(O)R 16a , —C(O)OR 16b  or —C(O)N(R 17a )R 17b ; 
       R 14  represents H, C 1-6  alkyl, -E-aryl, -E-Het 6 , —C(O)R 16a , —C(O)OR 16b , —S(O) 2 R 16c , —[C(O)] p N(R 17a )R 17b  or —C(NH)NH 2 ; 
       R 15  represents H, C 1-6  alkyl -E-aryl or —C(O)R 16d ; 
       R 16a  to R 16d  independently represent, at each occurrence when used herein, 
       C 1-6  alkyl (optionally substituted and/or terminated by one or more substituents selected from halo, aryl and Het 7 ), aryl, Het 8 , or R 16a  and R 16d  independently represent H; 
       R 17a  and R 17b  independently represent, at each occurrence when used herein, H or C 1-6  alkyl (optionally substituted and/or terminated by one or more substituents selected from halo, aryl and Het 9 ), aryl, Het 10 , or together represent C 3-6  alkylene, optionally interrupted by an O atom; 
       E represents, at each occurrence when used herein, a direct bond or C 1-4  alkylene; 
       p represents 1 or 2; 
       Het 6  to Het 10  independently represent five- to twelve-membered heterocyclic groups containing one or more heteroatoms selected from oxygen, nitrogen and/or sulfur, which groups are optionally substituted by one or more substituents selected from —OH, oxo, halo, cyano, nitro, C 1-6  alkyl, C 1-6  alkoxy, aryl aryloxy, N(R 18a )R 18b , —C(O)R 18c , —C(O)OR 18d , —C(O)N(R 18e )R 18f , —N(R 18g )C(O)R 18h  and —N(R 18i )S(O) 2 R 18j ; 
       R 18a  to R 18j  independently represent C 1-6  alkyl, aryl or R 18a  to R 18j  independently represent H; 
       A represents a direct bond, -J-, -J-N(R 19 )— or -J-O— (in which latter two groups, N(R 19 )— or O— is attached to the carbon atom bearing R 2  and R 3 ); 
       B represents -Z-, -Z-N(R 20 )—, —N(R 20 )-Z-, -Z-S(O) n —, -Z-O— (in which latter two groups, Z is attached to the carbon atom bearing R 2  and R 3 ), —N(R 20 )C(O)O-Z-, (in which latter group, —N(R 20 ) is attached to the carbon atom bearing R 2  and R 3 ) or —C(O)N(R 20 )— (in which latter group, —C(O) is attached to the carbon atom bearing R 2  and R 3 ); 
       J represents C 1-6  alkylene optionally substituted by one or more substituents selected from —OH, halo and amino; 
       Z represents a direct bond or C 1-4  alkylene; 
       n represents 0, 1 or 2; 
       R 19  and R 20  independently represent H or C 1-6  alkyl 
       G represents CH or N; 
       R 4  represents one or more optional substituents selected from —OH, cyano, halo, nitro, C 1-6  alkyl (optionally terminated by —N(H)C(O)OR 21a ), C 1-6  alkoxy, —N(R 22a )R 22b , —C(O)R 22c , —C(O)OR 22d , C(O)N(R 22e )R 22f , —N(R 22g )C(O)R 22h , —N(R 22i )C(O)N(R 22j )R 22k , —N(R 22m )S(O 2 )R 21b , —S(O) 2 R 21c , and/or —OS(O) 2 R 21d ; 
       R 21a  to R 21d  independently represent C 1-6  alkyl; 
       R 22a  and R 22b  independently represent H, C 1-6  alkyl or together represent C 3-6  alkylene, resulting in a four- to seven-membered nitrogen-containing ring; 
       R 22c  or R 22m  independently represent H or C 1-6  alkyl; and 
       wherein each aryl and aryloxy group, unless otherwise specified, is optionally substituted; 
       R 41  to R 46  independently represent H or C 1-3  alkyl; 
       or a protected derivative thereof, optionally in the form of a salt and/or a solvate. 
     
   
   
       47 . A compound as claimed in  claim 46 , wherein
 R 41  to R 46  all represent H;   G represents CH;   A represents a direct bond;   B represents a direct bond;   R 2  represents H or C 1-6  alkyl;   R 3  represents H or C 1-6  alkyl; and/or   R 4  is absent or represents one to three halo, methyl, methoxy or nitro groups.   
   
   
       48 . A compound as claimed in  claim 47 , wherein R 2  and R 3  both represent H, and R 4  is absent. 
   
   
       49 . A compound as claimed in  claim 46 , wherein the salt is a hydrochloride, sulfate, or hemisulfate salt. 
   
   
       50 . A compound as claimed in  claim 49 , wherein the salt is a dihydrochloride. 
   
   
       51 . A compound as claimed in  claim 50  wherein the salt is a dihydrochloride hydrate. 
   
   
       52 . A compound as claimed in  claim 51  wherein the hydrate is a hemihydrate. 
   
   
       53 - 75 . (canceled)