Compounds having beta2 adrenergic receptor agonist and muscarinic receptor antagonist activity

A process for preparing a compound of formula I:

• wherein
• one of G1 and G2 represents NH and the other represents S, NH, O or CH2;
• W represents O or NWa;
• where Wa is hydrogen or (1-4C)alkyl;
• each R1 is independently selected from (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (3-6C)cycloalkyl, cyano, halo, —OR1a, —C(O)OR1b, —SR1c, —S(O)R1d, —S(O)2R1e and —NR1fR1g;
• where each of R1a, R1b, R1c, R1d, R1e, R1f and R1g is independently hydrogen, (1-4C)alkyl or phenyl-(1-4C)alkyl;
• each R2 is independently selected from (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (3-6C)cycloalkyl, cyano, halo, —OR2a, —C(O)OR2b, —SR2c, —S(O)R2d, —S(O)2R2e and —NR2fR2g;
• where each of R2a, R2b, R2c, R2d, R2e, R2f and R2g is independently hydrogen, (1-4C)alkyl or phenyl-(1-4C)alkyl;
• each R3 is independently selected from (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (3-6C)cycloalkyl, cyano, halo, —OR3a, —C(O)OR3b, —SR3c, —S(O)R3d, —S(O)2R3e and —NR3fR3g;
• or two R3 groups are joined to form (1-3C)alkylene, (2-3C)alkenylene or oxiran-2,3-diyl;
• where each of R3a, R3b, R3c, R3d, R3e, R3f and R3g is independently hydrogen or (1-4C)alkyl;
• R4 represents a divalent hydrocarbon group containing from 4 to 28 carbon atoms and optionally containing from 1 to 10 heteroatoms selected independently from halo, oxygen, nitrogen and sulfur, provided that the number of contiguous atoms in the shortest chain between the two nitrogen atoms to which R4 is attached is in the range of from 4 to 16;
• R5 represents hydrogen or (1-4C)alkyl;
• R6 represents hydrogen or hydroxyl;
• each R7a and R7b is independently selected from hydrogen, (1-4C)alkyl, hydroxy and fluoro;
• a is 0 or an integer of from 1 to 3;
• b is 0 or an integer of from 1 to 3;
• c is 0 or an integer of from 1 to 4;
• d in 0 or an integer of from 1 to 5;
• and
• m is 0 or an integer of from 1 to 3;
• or a pharmaceutically acceptable salt or stereoisomer thereof;
• the process comprising:
• (a) reacting a compound of formula 1:
• or a salt thereof;
• with a compound of formula 2:
• wherein X1 represents a leaving group, R6a represents hydrogen or OP1, and P1 and P2 each independently represent a hydrogen atom or a hydroxyl-protecting group;
• (b) reacting a compound of formula 3:
• or salt thereof;
• with a compound of formula 4:
• wherein X2 represents a leaving group, R6b represents hydrogen or OP3, and P3 and P4 each independently represent a hydrogen atom or a hydroxyl-protecting group;
• (c) coupling a compound of formula 5:
• with a compound of formula 6:
• wherein XQa and XQb each independently represent functional groups that couple to form a group Q, P5a represents a hydrogen atom or an amino-protecting group, R6c represents hydrogen or OP5b, and P5b and P6 each independently represent a hydrogen atom or a hydroxyl-protecting group;
• (d) for a compound of formula I wherein R5 represents a hydrogen atom, reacting a compound of formula 3 with a compound of formula 7a or 7b:
• or a hydrate thereof, in the presence of a reducing agent, wherein P7 represents a hydrogen atom or a hydroxyl-protecting group;
• (e) reacting a compound of formula 1 with a compound of formula 8:
• or a hydrate thereof, in the presence of a reducing agent, wherein R6d represents hydrogen or OP8, P8 and P9 each independently represent a hydrogen atom or a hydroxyl-protecting group, P10 represents a hydrogen atom or an amino-protecting group, and R4′ represents a residue that, together with the carbon to which it is attached, affords a group R4 upon completion of the reaction;
• (f) reacting a compound of formula 9:
• wherein X3 represents a leaving group, with a compound of formula 10:
• wherein R6e represents hydrogen or OP11, P11 and P12 each independently represent a hydrogen atom or a hydroxyl-protecting group, and P13 represents a hydrogen atom or an amino-protecting group;
• or
• (g) reacting a compound of formula 11:
• or a hydrate thereof;
• wherein R4′ represents a residue that, together with the carbon to which it is attached, affords a group R4 upon completion of the reaction;
• with a compound of formula 10 in the presence of a reducing agent;
• and then
• removing any protecting group P1, P2, P3, P4, P5a, P5b, P6, P7, P8, P9, P10, P11, P12 or P13 to provide a compound of formula I