Oxabispidine compounds useful in the treatment of cardiac arrhythmias

A process for the preparation of a compound of formula I

• wherein
• R1 represents —C(O)XR7, —C(O)N(R8)R5d or —S(O)2R9;
• represents H, C1-6 alkyl which alkyl group is optionally substituted and/or terminated by one or more substituents selected from —OH, halo, cyano, nitro, aryl and Het2, aryl and Het3, or R5d, together with R8, 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;
• R7 represents C1-12 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 and Het4;
• R8 represents H, C1-12 alkyl, C1-6 alkoxy which alkyl and alkoxy 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-Het5, -D-N(H)C(O)R11a, -D-S(O)2R12a, -D-C(O)R11b, -D-C(O)OR12b, -D-C(O)N(R11c)R11d, or R8, together with R5d, 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;
• R11a to R11d independently represent H, C1-6 alkyl which alkyl group is optionally substituted and/or terminated by one or more substituents selected from —OH, halo, cyano, nitro and aryl, aryl, or R11c and R11d together represent C3-6 alkylene;
• R9, R12a and R12b independently represent C1-6 alkyl which alkyl group is optionally substituted and/or terminated by one or more substituents selected form —OH, halo, cyano, nitro and aryl, or aryl;
• D represents a direct bond or C1-6 alkylene;
• X represents O or S;
• R2 represents H, halo, C1-6 alkyl, —OR13, -E-N(R14)R15 or, together with
• R3, represents ═O;
• R3 represents H, C1-6 alkyl or, together with R2, represents ═O;
• R13 represents H, C1-6 alkyl, -E-aryl, -E-Het6, —C(O)R16a, —C(O)OR16b or —C(O)N(R17a)R17b;
• R14 represents H, C1-6 alkyl, -E-aryl, -E-Het6, —C(O)R16a, —C(O)OR16b, —S(O)2R16c, —[C(O)]pN(R17a)R17b or —C(NH)NH2;
• R15 represents H, C1-6 alkyl, -E-aryl or —C(O)R16d;
• R16a to R16d independently represent, at each occurrence when used herein,
• C1-6 alkyl which alkyl group is optionally substituted and/or terminated by one or more substituents selected from halo, aryl and Het7, aryl, Het8, or R16a and R16d independently represent H;
• R17a and R17b independently represent, at each occurrence when used herein, H or C1-6 alkyl which alkyl group is optionally substituted and/or terminated by one or more substituents selected from halo, aryl and Het9, aryl, Het10, 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;
• Het1 to Het10 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, C1-6 alkyl, C1-6 alkoxy, aryl, aryloxy, —N(R18a)R18b, —C(O)R18c, —C(O)OR18d, —C(O)N(R18e)R18f, —N(R18g)C(O)R18h and —N(R18i)S(O)2R18j;
• R18a to R18j independently represent C1-6 alkyl, aryl or R18a to R18j independently represent H;
• A represents a direct bond, -J-, -J-N(R19)— or -J-O— in which latter two groups, N(R19)— or O— is attached to the carbon atom bearing R2 and R3;
• B represents -Z-, -Z-N(R20)—, —N(R20)-Z-, -Z-S(O)n—, -Z-O— in which latter two groups, Z is attached to the carbon atom bearing R2 and R3, —N(R20)C(O)O-Z- in which latter group, —N(R20) is attached to the carbon atom bearing R2 and R3, or —C(O)N(R20)— in which latter group, —C(O) is attached to the carbon atom bearing R2 and R3;
• J represents C1-6 alkylene optionally substituted by one or more substituents selected from —OH, halo and amino;
• Z represents a direct bond or C1-4 alkylene;
• n represents 0, 1 or 2;
• R19 and R20 independently represent H or C1-6 alkyl;
• G represents CH or N;
• R4 represents one or more optional substituents selected from —OH, cyano, halo, nitro, C1-6, alkyl which alkyl group is optionally terminated by —N(H)C(O)OR21a, C1-6 alkoxy, —N(R22a)R22b, —C(O)R22c, —C(O)OR22d, —C(O)N(R22e)R22f, —N(R22g)C(O)R22h, —N(R22i)C(O)N(R22j)R22k, —N(R22m)S(O2)R21b, —S(O)2R21c, and/or —OS(O)2R21d;
• R21a to R21d independently represent C1-6 alkyl;
• R22a and R22b independently represent H, C1-6 alkyl or together represent C3-6 alkylene, resulting in a four- to seven-membered nitrogen-containing ring;
• R22c or R22m independently represent H or C1-6 alkyl;
• and
• R41 to R46 independently represent H or C1-3 alkyl;
• wherein each aryl and aryloxy group, unless otherwise specified, is optionally substituted;
• or a pharmaceutically acceptable derivative thereof,
• which process comprises:
• reacting compound of formula XLVII,
• wherein A, B, G, R1, R2, R3, R4 and R41 to R46 are as defined above with a dehydrating agent to cause dehydrative cyclisation to form the compound of formula I.