Novel Oxabispidine Compounds And Their Use In The Treatment Of Cardiac Arrhythmias

Abstract

There is provided compounds of formula I, wherein R 1 , R 2 , 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 - 38 . (canceled)  
     
     
         39 . of formula I  
       
         
           
           
               
               
           
         
       
       wherein: 
 G represents CH or N;  
 R 41  to R 46 , independently, represent H or C 1-3  alkyl;  
 A represents C 2-6  alkylene optionally interrupted by —S(O) 2 N(R 18a )— or —N(R)S(O) 2 — and/or optionally substituted by one or more substituents selected from —OH, halo, and amino;  
 R 18a  represents H or C 1-6  alkyl;  
 R 2  represents —S(O) 2 R 3a , —C(O)OR 3b , —C(O)R 3c , —C(O)N(R 3d )(R 3e ) or —S(O) 2 N(R 3f )(R 3g );  
 R 3a  to R 3g , independently, represent C 1-6  alkyl (optionally substituted by one or more substituents selected from halo, -E-aryl, -E-Het 8 , —C(O)R 16a , —C(O)OR 16b  and —C(O)N(R 16c )R 16d ), aryl or Het 9 , or R 3c  and R 3d  to R 3g  independently represent H;  
 E represents, at each occurrence when used herein, a direct bond or C 1-4  alkylene;  
 Het 1  to Het 11 , 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 17a )R 17b , —C(O)R 17c , —C(O)OR 17d , —C(O)N(R 17e )R 17f ,  
 —N(R 17g )C(O)R 17h , —S(O) 2 N(R 17i )R 17j  and —N(R 17k )S(O) 2 R 17l ;  
 R 16a  to R 16d , independently, represent at each occurrence when used herein, H, C 1-6  alkyl (optionally substituted by one or more substituents selected from halo, aryl and Het 10 ), aryl, Het 11 , or R 16c  and R 16d  together represent C 3-6  alkylene, optionally interrupted by an O atom;  
 R 17a  to R 17l , independently, represent C 1-6  alkyl, aryl or R 17a  to R 17k  independently represent H;  
 B represents -Z 1 -{[C(O)] a C(H)(R 19a )} b —, -Z 2 -[C(O)] c N(R 19b )—, -Z 2 -S(O) n —, -Z 2 -N(R 18c )S(O) 2 —, -Z 2 -S(O) 2 N(R 18d )— or -Z 2 -O— (in which six groups Z 1  or Z 2  is attached to the nitrogen atom bearing R 2 );  
 a, b, and c, independently, represent 0 or 1;  
 n represents 0, 1, or 2;  
 Z 1  represents a direct bond or C 1-4  alkylene, optionally interrupted by —N(R 18e )S(O) 2 — or —S(O) 2 N(R 18f )—;  
 Z 2  represents, at each occurrence when used herein, C 2-4  alkylene, optionally interrupted by —N(R 18g )S(O) 2 — or —S(O) 2 N(R 18h )—;  
 R 18c  to R 18h , independently, represent H or C 1-6  alkyl;  
 R 19a  represents H or, together with a single R 4  substituent at a position on the phenyl or pyridyl group that is ortho- to the position at which the group B is attached, R 19a  represents C 2-4  alkylene optionally interrupted or terminated by O, S or N(R 20 );  
 R 19b  represents H, C 1-6  alkyl or, together with a single R 4  substituent at a position on the phenyl or pyridyl group that is ortho- to the position at which the group B is attached, R 19b  represents C 2-4  alkylene;  
 R 20  represents H or C 1-6  alkyl;  
 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)R 21b , —S(O) 2 N(R 22n )R 22o , —S(O) 2 R 21c , —OS(O) 2 R 21d  and aryl, and an R 4  substituent in a position on the phenyl or pyridyl group that is ortho- to the position at which the group B is attached may  
 (i) together with R 19a , represent C 2-4  alkylene optionally interrupted or terminated by O, S or N(R 20 ), or  
 (ii) together with R 19b , represent C 2-4  alkylene;  
 R 20  represents H or C 1-6  alkyl;  
 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; and  
 R 22c  to R 22o , independently, represent H or C 1-6  alkyl;  
 R 1  represents C 1-12  alkyl (which alkyl group is optionally substituted by one or more groups selected from halo, cyano, nitro, aryl, Het 1 , —C(O)R 5a , —OR 5b , —N(R 6 )R 5c , —C(O)XR 7 ,  
 —C(O)N(R 8a )R 5d , —OC(O)N(R 8b )R 5e , —S(O) 2 R 9a , —S(O) 2 N(R 9b )R 9c , and —N(R 9b )S(O) 2 R 9d );  
 X is O or S;  
 R 5a  to R 5e , independently, represent at each occurrence when used herein, H, C 1-6  alkyl (which latter group is optionally substituted by one or more substituents selected from —OH, halo, cyano, nitro, aryl, aryloxy, Het 2 , —S(O) 2 N(R 9b )R 9c  and —N(R 9b )S(O) 2 R 9d ), aryl or Het 3 , or R 5d  or R 5e , together with, respectively, R 8a  or R 8b , may represent C 3-6  alkylene (which alkylene group is optionally interrupted by an O atom and/or is optionally substituted by one or more C 1-3  alkyl groups);  
 R 6  represents H, C 1-6  alkyl (optionally substituted by one or more substituents selected from —OH, halo, cyano, nitro, aryl, —S(O) 2 N(R 9b )R 9c  and —N(R 9b )S(O) 2 R 9d ), aryl, —C(O)R 10a ,  
 —C(O)OR 10b , —C(O)N(R 10c )R 10d  or —S(O) 2 R 10e ;  
 R 10a  to R 10e , independently, represent C 1-6  alkyl (optionally substituted by one or more substituents selected from —OH, halo, cyano, nitro and aryl), aryl, or R 10a , R 10c  or R 10d  represents H;  
 R 7  represents, at each occurrence when used herein, C 1-12  alkyl (optionally substituted by one or more substituents selected from —OH, halo, cyano, nitro, aryl, C 1-6  alkoxy, Het 4 ,  
 —S(O) 2 N(R 9b )R 9c  and —N(R 9b )S(O) 2 R 9d );  
 R 8a  and R 8b  independently represent H, C 1-12  alkyl, C 1-6  alkoxy (which latter two groups are optionally substituted by one or more substituents selected from —OH, halo, cyano, nitro, C 1-4  alkyl, C 1-4  alkoxy, —S(O) 2 N(R 9a )R 9c  and —N(R 9b )S(O) 2 R 9d ), -D-aryl, -D-aryloxy, -D-Het 5 , -D-N(H)C(O)R 11a , -D-S(O) 2 R 12a , -D-C(O)R 11b , -D-C(O)OR 12b  -D-C(O)N(R 11c )R 11d , or R 8a  or R 8b , together with, respectively, R 5d  or R 5e , may represent C 3-6  alkylene (which alkylene group is optionally interrupted by an O atom and/or is optionally substituted by one or more C 1-3  alkyl groups);  
 R 9a  represents, at each occurrence when used herein, C 1-6  alkyl (optionally substituted by one or more substituents selected from —OH, halo, cyano, nitro, aryl, —S(O) e N(R 9b )R 9c  and —N(R 9b )S(O) 2 R 9d ) or aryl;  
 R 9b  represents, at each occurrence when used herein, H or C 1-6  alkyl;  
 R 9c  and R 9d , independently, represent at each occurrence when used herein, C 1-6  alkyl (optionally substituted by one or more substituents selected from —OH, halo, cyano, nitro, aryl and Het 6 ), aryl or Het 7 , or R 9c  represents H;  
 R 11a  to R 11d , independently, represent H, C 1-6  alkyl (optionally substituted by one or more substituents selected from —OH, halo, cyano, nitro and aryl), aryl, or R 11c  and R 11d  together represent C 3-6  alkylene;  
 R 12a  and R 12b , independently, represent C 1-6  alkyl (optionally substituted by one or more substituents selected from —OH, halo, cyano, nitro and aryl) or aryl; and  
 D represents, at each occurrence when used herein, a direct bond or_C 1-6  alkylene;  
 wherein each aryl and aryloxy group, unless otherwise specified, is optionally substituted;  
 in combination with another drug for use as a medicament for the treatment of arrhythmia or a cardiovascular disorder.  
 
     
     
         40 .- 45 . (canceled)  
     
     
         46 . A compound of  claim 39  in combination with an anticoagulant.  
     
     
         47 . A compound of  claim 46  wherein the anticoagulant is a substance selected from aspirin, warfarin, enoxaparin, heparin, low molecular weight heparin, cilostazol, clopidogrel, ticlopidine, tirofiban, abciximab, dipyridamole, plasma protein fraction, human albumin, low molecular weight dextran, hetastarch, reteplase, alteplase, streptokinase, urokinase, dalteparin, filgrastin, immunoglogulin, ginkolide B, hirudins, foropafant, rocepafant, bivalirudin, dermatan sulfate mediolanum, eptilibatide, tirofiban, thrombomodulin, abcxmab, low molecular weight dermatan sulfate-opocrin, eptacog alfa, argatroban, fondaparinux sodium, tifacogin, lepirudin, desirudin, OP2000, roxifiban, parnaparin sodium, human hemoglobin, bovine hemoglobin, human hemoglobin, antithrombin III, RSR 13, heparin-oral transgenic antithrombin III, H37695, enoxaparin sodium, mesoglycan, CTC 111, bivalirudin, or any combination thereof.  
     
     
         48 . A compound of  claim 47  wherein the anticoagulant is aspirin or warfarin.  
     
     
         49 . A compound of  claim 46  wherein the anticoagulant is a thrombin inhibitor.  
     
     
         50 . A compound of  claim 49  wherein the thrombin inhibitor is a low molecular weight thrombin inhibitor.  
     
     
         51 . A compound of  claim 50  wherein the low molecular weight thrombin inhibitor is a low molecular weight peptide-based, amino acid-based, and/or peptide analogue-based, thrombin inhibitor.  
     
     
         52 . A compound of  claim 51  wherein the low molecular weight peptide-based thrombin inhibitor is a gatran.  
     
     
         53 . A compound of  claim 52  wherein the gatran is inogatran or melagatran.