3,8-Diazabicyclo[3.2.1]octanes and their use in the treatment of cardiac arrhythmias

The use of a compound of formula I,

• 25
• wherein
• one of R1 and R2 represents R1a and the other represents a fragment of the formula Ia,
• 26
• R1a represents C1-12 alkyl (optionally substituted and/or terminated by one or more groups selected from halo, cyano, nitro, aryl, Het1, —C(O)R7a, —OR7b, —N(R8)R7c, —C(O)XR9, —C(O)N(R10)R7d and —S(O)2R11), Het2, —C(O)R7a, —C(O)XR9, —C(O)N(R10)R7d or —S(O)2R11;
• R7a to R7d independently represent, at each occurrence when used herein, H, C1-6 alkyl (optionally substituted and/or terminated by one or more substituents selected from —OH, C1-6 alkoxy, halo, cyano, nitro, aryl, Het3 and —NHC(O)R12), aryl or Het, or R7d, together with R10), represents C3-6 alkylene (which alkylene group is optionally interrupted by an O atom and/or is optionally substituted by one or more C1-3 alkyl groups);
• R12 represents H, C1-4 alkyl (optionally substituted and/or terminated by one or more substituents selected from halo, cyano, aryl and —NHC(O)R13) or aryl;
• R13 represents H, C1-4 alkyl or aryl;
• R8 represents H, C1-6 alkyl (optionally substituted and/or terminated by one or more substituents selected from —OH, halo, cyano, nitro and aryl), aryl, —C(O)R14a or —C(O)OR14b;
• R14a and R14b represent C1-6 alkyl (optionally substituted and/or terminated by one or more substituents selected from —OH, halo, cyano, nitro and aryl) or aryl, or R14a represents H;
• X represents O or S;
• R9 represents, at each occurrence when used herein, aryl or C1-2 alkyl (which alkyl group is optionally substituted and/or terminated by one or more substituents selected from —OH, halo, cyano, nitro, aryl, C1-6 alkoxy, —SO2R15 and Het5);
• R15 represents C1-6 alkyl or aryl;
• R10 represents, at each occurrence when used herein, H, C1-12 alkyl, C1-6 alkoxy (which latter two groups are optionally substituted and/or terminated by one or more substituents selected from —OH, halo, cyano, nitro, C1-4 alkyl and C1-4 alkoxy), -D-aryl, -D-aryloxy, -D-Het6, -D-N(H)C(O)R16a, -D-S(O)2R17a, -D-C(O)R16b, -D-C(O)OR17b, -D-C(O)N(R16c)R16d, or R10, together with R7d, represents C3-6 alkylene (which alkylene group is optionally interrupted by an O atom and/or is optionally substituted by one or more C1-3 alkyl groups);
• R16a to R16d independently represent H, C1-6 alkyl (optionally substituted and/or terminated by one or more substituents selected from —OH, halo, cyano, nitro and aryl), aryl, or R16c and R16d together represent C3-6 alkylene;
• R17a and R17b independently represent C1-6 alkyl (optionally substituted and/or terminated by one or more substituents selected from —OH, halo, cyano, nitro and aryl) or aryl;
• D represents a direct bond or C1-6 alkylene;
• R11 represents, at each occurrence when used herein, C1-6 alkyl (optionally substituted and/or terminated by one or more substituents selected from —OH, halo, cyano, nitro and aryl), aryl or Het7;
• R3 represents H, halo, C1-6 alkyl, -E-OR18, -E-N(R19)R20 or, together with R4, represents ═O;
• R4 represents H, C1-6 alkyl or, together with R3, represents ═O;
• R18 represents H, C1-6 alkyl, -E-aryl, -E-Het8, —C(O)R21a, —C(O)OR21b or C(O)N(R22a)R22b;
• R19 represents H, C1-6 alkyl, -E-aryl, -E-Het8, —C(O)R21a, —C(O)OR21b, —S(O)2R21c, [C(O)]pN(R22a)R22b or —C(NH)NH2;
• R20 represents H, C1-6 alkyl, -E-aryl or 3C(O)R21d;
• R21a to R21d independently represent, at each occurrence when used herein, C1-6 alkyl (optionally substituted and/or terminated by one or more substituents selected from halo, aryl and Het9), aryl, Het10, or R21a and R21d independently represent H;
• R22a and R22b independently represent, at each occurrence when used herein, H or C1-6 alkyl (optionally substituted and/or terminated by one or more substituents selected from halo, aryl and Het11), aryl, Het12, or together represent C3-6 alkylene, optionally interrupted by an O atom;
• E represents, at each occurrence when used herein, a direct bond or C1-4 alkylene;
• p represents 1 or 2;
• A represents -G-, -J-N(E24)- or -J-O— (in which latter two groups, N(R24)— or O— is attached to the carbon atom bearing R3 and R4);
• B represents -Z-, -Z-N(R25)—, —N(R25)-Z-, -Z-S(O)n—, -Z-O— (in which latter two groups, Z is attached to the carbon atom bearing R3 and R4);
• G represents C1-6 alkylene;
• J represents C2-6 alkylene;
• Z represents a direct bond or C1-4 alkylene;
• R24 and R25 independently represent H or C1-6 alkyl;
• R5 represents aryl or Het13, both of which groups are optionally substituted by one or more substituents selected from —OH, cyano, halo, C1-6 alkyl (optionally terminated by —N(H)C(O)OR2Ga), C1-6 alkoxy, Het1, aryl, —C(O)R27cC(O)OR27d, —C(O)N(R27e)R27f, —N(R27i)C(O)N(R27j)R27k, —S(O)nR26c, —OS(O)2R26d, —S(O)2N(R27n)R27pand (in the case of Het13 only) oxo;
• Het13 represents a four- to twelve-membered heterocyclic group containing one or more heteroatoms selected from oxygen, nitrogen and/or sulfur;
• Het1 to Het12 independently represent, at each occurrence when used herein, four- to twelve-membered heterocyclic groups containing one or more heteroatoms selected from oxygen, nitrogen and/or sulfur, which heterocyclic groups are optionally substituted by one or more substituents including ═O, —OH, cyano, halo, nitro, C1-6 alkyl (optionally terminated by —N(H)C(O)OR26a), C1-6 alkoxy, Het1, aryl, —N(R27d)R27b, -G(O)R27c, —C(O)OR27d, C(O)N(R27c)R27f, —N(R27g)C(O)R27h, —N(R27i)C(O)N(R27j)R21k, —N(R27m)S(O)2R26h, —S(O)nR26c, —OS(O)2R26d and —S(O)2N(R27n)R27p;
• R26a to R26d independently represent, at each occurrence when used herein, C1-6 alkyl;
• R27a to R27p independently represent, at each occurrence when used herein, H or C1-6 alkyl;
• n represents, at each occurrence, 0, 1 or 2;
• and
• Ra to Rh independently represent H or C1-4 alkyl;
• wherein each aryl and aryloxy group, unless otherwise specified, is optionally substituted;
• or a pharmaceutically acceptable derivative thereof;
• provided that:
• (a) when R4 represents H or C1-4 alkyl;
• and
• A represents -J-N(R24)— or -J-O—;
• then B does not represent —N(R25)—, —S(O)n—, —O— or —N(R25)-Z- (in which latter group —N(R25) is attached to the carbon atom bearing R3 and R4);
• (b) when R3 represents -E-OR18 or -E-N(R19)R20 in which E represents a direct bond, then:
• (i) A does not represent -J-N(R24)— or -J-O—;
• and
• (ii) B does not represent —N(R25)—, —S(O)n—, —O— or —N(R25)-Z- (in which latter group —N(R25) is attached to the carbon atom bearing R3 and R4);
• for the manufacture of a medicament for the treatment or prophylaxis of cardiac arrhythmias.