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 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 - 51 . (canceled) 
   
   
       52 . A compound of formula I, 
     
       
         
         
             
             
         
       
     
     wherein:
 R 1  represents straight- or branched-chain C 1-3  alkyl substituted by OR 5c , phenyl (optionally substituted by one or two substituents selected from halo, cyano, methyl, methoxy (which latter two groups are optionally substituted by one to three fluoro atoms), —C(O)CH 3  and —S(O) 2 CH 3 ), Het 1 , —C(O)R 5b , —N(H)C(O)O—C 3-4  alkyl, —C(O)N(H)R 8a , —OC(O)N(H)—C 3-4  alkyl, —S(O) 2 N(H)—C 3-4  alkyl, or —N(H)S(O) 2 R 9d ; 
 Het 1  represents an aromatic five- or six-membered heterocyclic group containing one or two heteroatoms selected from oxygen, nitrogen, and sulfur, which group is optionally substituted by one or two substituents selected from chloro, methyl, and methoxy; 
 R 5b  and R 5c , independently, represent phenyl optionally substituted by one or two substituents selected from cyano, methyl, and methoxy; 
 R 8a  represents tert-butyl, CH 2 -phenyl, or C(CH 3 ) 2 -phenyl; 
 R 9d  represents C 1-4  alkyl (which is optionally substituted by one or more fluoro atoms), (CH 2 ) 1-2 -phenyl (the phenyl part of which is optionally substituted by one to three substituents selected from chloro, methyl, and methoxy (which latter two groups are optionally substituted by one or more fluoro atoms)), phenyl (optionally substituted by one or more substituents selected from fluoro, methyl, and methoxy (which latter two groups are optionally substituted by one or more fluoro atoms)) or Het 7 ; 
 Het 7  represents a five-membered heterocyclic group containing one nitrogen atom and optionally containing one further heteroatom selected from oxygen, nitrogen, and sulfur, which heterocyclic group is optionally substituted by one to three methyl groups; 
 R 2  represents H or —OH; 
 R 3  represents H, C 1-6  alkyl or, together with R 2 , represents ═O; 
 A represents direct bond or C 1-3  alkylene; 
 B represents direct bond, C 1-3  alkylene, C 1-3  alkoxy, —N(H)S(O) 2 — (in which latter group, —N(H) is attached to the carbon atom bearing R 2  and R 3 ) or —(CH 2 ) 0-1 —O— (in which latter group, —CH 2 — is attached to the carbon atom bearing R 2  and R 3 ); 
 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 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 20a , represent C 2-4  alkylene optionally interrupted or terminated by O, S or N(H) or N(C 1-6  alkyl), or 
 (ii) together with R 20b , represent C 2-4  alkylene; 
 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  to R 22o , independently, represent H or C 1-6  alkyl; and 
 R 41  to R 46 , independently, represents H or C 1-6  alkyl; 
 
     or a pharmaceutically acceptable derivative thereof. 
   
   
       53 . A compound of formula I, 
     
       
         
         
             
             
         
       
     
     wherein:
 R 1  represents C 2-3  alkyl, which alkyl group is substituted by at least one —S(O) 2 N(R 9b )R 9c  and/or —N(R 9b )S(O) 2 R 9d  group; 
 R 9b  represents H or C 1-3  alkyl; 
 R 9c  and R 9d  each, independently, represent hydrogen, C 1-6  alkyl (optionally substituted by one or more halo groups), aryl (optionally substituted by one or more halo, cyano, methoxy, fluoromethoxy, difluoromethoxy or trifluoromethoxy groups) or Het 7 ; 
 Het 7  represents a five-membered heterocyclic group containing one nitrogen atom and optionally containing one further heteroatom selected from oxygen, nitrogen, and sulfur, which heterocyclic group is optionally substituted by one to three methyl groups; 
 R 2  and R 3  each, independently, represent hydrogen or hydroxy; 
 A represents —CH 2 —; 
 B represents a direct bond, C 1-3  alkylene or C 1-3  alkoxy (in which the oxygen is attached to the phenyl group that is optionally substituted with R 4 ); 
 G represents CH; 
 R 41  to R 46  represents hydrogen; and 
 R 4  represents one or more optional substituents selected from cyano and halo, and an R 4  substituent is in a position on the phenyl group that is ortho- and/or para- to the position at which the group B is attached. 
 
   
   
       54 . A compound of formula I, 
     
       
         
         
             
             
         
       
     
     wherein:
 R 1  represents a C 2 -C 5  alkyl group, which is substituted by one or more sulfonamide groups selected from 4-cyanobenzenesulfonamide, propane-2-sulfonamide, 1-phenylmethanesulfonamide, propane-1-sulfonamide, 4-fluorobenzenesulfonamide, benzenesulfonamide, 2,4-difluorobenzenesulfonamide, methanesulfonamide, 3-chloro-1-phenylmethanesulphonamide, trifluoromethanesulfonamide, 1-methyl-1H-imidazole-4-sulfonamide, butane-1-sulfonamide, 1-[4-(trifluoromethyl)phenyl]methanesulfonamide, 3,5-dimethylisoxazole-4-sulfonamide, 2-(trifluoromethoxy)benzenesulfonamide, [2-(trifluoromethoxy)phenyl]methanesulfonamide, 2,3-dihydro-1-benzofuran-5-sulfonamide, 2-cyanobenzenesulfonamide, 4-methoxybenzenesulfonamide, 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonamide, 3-fluorobenzenesulphonamide, 5-methylisoxazole-4-sulfonamide, 3-cyanobenzenesulfonamide, 4-cyano-1-phenylmethanesulphonamide, and 2-fluorobenzenesulphonamide; 
 R 41  to R 46  are hydrogen; 
 the group 
 
     
       
         
         
             
             
         
       
     
     represents methylene, ethylene, propylene, butylene, or 2-hydroxypropylene, optionally terminated or interrupted with an oxygen atom and/or optionally interrupted with a —SO 2 —NH— or —NH—SO 2 — group; and
 the group 
 
     
       
         
         
             
             
         
       
     
     represents phenyl, 4-cyanophenyl, 3,4-bis(difluoromethoxy)phenyl, 4-fluorophenyl, 4-(difluoromethoxy)phenyl, 2-fluorophenyl, 2,5-difluorophenyl, 3,4-difluorophenyl, 4-cyano-2-fluorophenyl, 3,4-difluorophenyl, 2-cyanophenyl, 3-fluorophenyl, 4-cyano-2,6-difluorophenyl, 2,6-difluorophenyl, 3-cyanophenyl, 4-chlorophenyl, 4-(trifluoromethyl)phenyl, 2,4-difluorophenyl, 2-(trifluoromethoxy)phenyl, 3-chlorophenyl or 4-methoxyphenyl. 
   
   
       55 . A compound which is N-(2-{7-[2-(4-cyano-2-fluoro-phenoxy)-ethyl]-9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl}-ethyl)-2,4-difluoro-benzenesulfonamide, 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable derivative thereof. 
   
   
       56 . A pharmaceutical formulation comprising a compound according to any one of  claims 52  to  55  in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier. 
   
   
       57 . A method of treating an arrhythmia in a person, comprising administering to the person a compound according to any one of  claims 52  to  55 . 
   
   
       58 . The method according to  claim 57  wherein the arrhythmia is an atrial or a ventricular arrhythmia. 
   
   
       59 . The method according to  claim 57  wherein the compound is administered in combination with another drug for use as a medicament for the treatment of the arrhythmia or another cardiac disorder. 
   
   
       60 . A process for the preparation of a compound according to  claim 52 , comprising:
 a) reacting a compound of formula II,   
     
       
         
         
             
             
         
       
       wherein R 2 , R 3 , R 4 , R 41  to R 46 , A, B and G are as recited in  claim 52 , or a salt thereof, with a compound of formula XXXII,
   C 1-4 alkyl-OC(O)N—C 1-2 alkyl-L 1   XXXII 
 
       wherein R 1  is recited in  claim 52  and L 1  represents a leaving group; or 
       b) reacting a compound of formula IV, 
     
     
       
         
         
             
             
         
       
       wherein R 1a  represents C 1-3  alkylene, which group is optionally substituted by one or more substituents as recited in  claim 52  in respect of R 1  and R 2 , R 3 , R 4 , R 41  to R 46 , A, B and G as recited in  claim 52  and R 9b  is H or C 1-6  alkyl, or a salt thereof, with a compound of formula V,
   L 2 -S(O) 2 R 9d   V 
 
       wherein R 9d  is as recited in  claim 52  and L 2  represents a leaving group. 
     
   
   
       61 . The method according to  claim 60 , wherein:
 the compound of formula II is 3-fluoro-4-[2-(9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl)-ethoxy]-benzonitrile hydrochloride,   
     
       
         
         
             
             
         
       
       the compound of formula XXXII is tert-butyl 2-bromoethylcarbamate, 
     
     
       
         
         
             
             
         
       
       the compound of formula I resulting from process step a) is (2-{7-[2-(4-cyano-2-fluoro-phenoxy)-ethyl]-9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl}-ethyl)-carbamic acid tert-butyl ester, 
     
     
       
         
         
             
             
         
       
     
     the compound of formula IV is 4-{2-[7-(3-amino-propyl)-9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl]-ethoxy}-3-fluoro-benzonitrile hydrochloric acid salt, 
     
       
         
         
             
             
         
       
       the compound of formula V is 2,4-difluorobenzenesulfonyl chloride 
     
     
       
         
         
             
             
         
       
       the compound of formula I resulting from process step b) is N-(2-{7-[2-(4-cyano-2-fluoro-phenoxy)-ethyl]-9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl}-ethyl)-2,4-difluoro-benzenesulfonamide, 
     
     
       
         
         
             
             
         
       
     
   
   
       62 . A compound selected from: 
     7-[2-(4-cyano-2-fluoro-phenoxy)-ethyl]-9-oxa-3,7-diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester; 
     3-fluoro-4-[2-(9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl)-ethoxy]-benzonitrile hydrochloride; 
     (2-{7-[2-(4-cyano-2-fluoro-phenoxy)-ethyl]-9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl}-ethyl)-carbamic acid tert-butyl ester; 
     4-{2-[7-(2-amino-ethyl)-9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl]-ethoxy}-3-fluoro-benzonitrile trifluoroacetic acid salt; and 
     4-{2-[7-(2-amino-ethyl)-9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl]-ethoxy}-3-fluoro-benzonitrile hydrochloric acid salt.