Biphenyl compounds useful as muscarinic receptor antagonists

1. A compound of formula I:

wherein:

a is 0 or 1;

R 1 is halo;

b is 0 or 1;

R 2 is halo;

m is 0 or 1;

R 4 is selected from hydrogen and (1-4C)alkyl;

s is 0, 1 or 2;

Ar 1 represents a divalent species of a (3-5C)heteroarylene group selected from imidazole, thiazole, oxazole, pyrazole, isoxazole, isothiazole, pyrazine, pyridazine, and pyrimidine;

t is 0, 1 or 2;

X 1 is selected from (1-3C)alkylene, —C(O)(1-3C)alkylene, (1-3C)alkyleneC(O)—, —SO 2 —, —SO 2 (1-3C)alkylene and (1-3C)alkyleneSO 2 —; where the alkylene group in any X 1 is optionally substituted with 1 or 2 substituents independently selected from (1-4C)alkyl and —NR Xa R Xb ; wherein R Xa and R Xb independently selected from hydrogen and (1-4-alkyl);

R 7 is selected from hydrogen and (1-4C)alkyl;

or a pharmaceutically acceptable salt or solvate or stereoisomer thereof.

2. The compound of claim 1 , wherein a and b each represent 0.

3. The compound of claim 1 , wherein m is 0, and t is 1.

4. The compound of claim 1 , wherein s is 0.

5. The compound of claim 1 , wherein X 1 is selected from —CH 2 — and —CH 2 CH 2 —.

6. The compound of claim 1 , wherein R 4 is hydrogen or methyl.

7. The compound of claim 1 , wherein R 7 is hydrogen or methyl.

8. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 1 .

9. The pharmaceutical composition of claim 8 , wherein the composition further comprises a therapeutically effective amount of an agent selected from β 2 adrenergic receptor agonists, steroidal anti-inflammatory agents, phosphodiesterase-4 inhibitors, and combinations thereof.

10. The pharmaceutical composition of claim 9 , wherein the composition comprises a therapeutically effective amount of a β 2 adrenergic receptor agonist and a steroidal anti-inflammatory agent.

11. A process for preparing a compound as claimed in claim 1 , the process comprising:

(a) reacting a compound of formula II:

or a salt thereof, with a compound of formula III:

wherein Z 1 represents a leaving group, and P 1 represents a hydrogen atom or a hydroxyl-protecting group;

(b) coupling a compound of formula IV:

with a compound of formula V:

or a reactive derivative thereof, wherein P 2 represents a hydrogen atom or a hydroxyl-protecting group;

(c) reacting a compound of formula VI:

with a compound of formula VII:

wherein Z 2 represents a leaving group; and P 3 represents a hydrogen atom or a hydroxyl-protecting group;

(d) reacting a compound of formula II with a compound of formula VIII:

wherein P 4 represents a hydrogen atom or a hydroxyl-protecting group, in the presence of a reducing agent; or

(e) for a compound of formula I in which X 1 represents (1-3C)alkylene, reacting a compound of formula VI with a compound of formula IX:

wherein X 1a represents a bond or (1-2C)alkylene; and P 5 represents a hydrogen atom or a hydroxyl-protecting group, in the presence of a reducing agent;

(f) for a compound of formula I in which t is 1, reacting a compound of formula X:

with a compound of formula XI:

wherein P 6 represents a hydrogen atom or a hydroxyl-protecting group, in the presence of a reducing agent; and then

(g) removing any protecting group P 1 , P 2 , P 3 , P 4 , P 5 , or P 6 to provide a compound of formula I.

12. The process of claim 11 , wherein the process further comprises forming a pharmaceutically acceptable salt of the compound of formula I.

13. A method of producing bronchodilation in a patient, the method comprising administering to a patient a bronchodilation-producing amount of a compound of claim 1 .

14. A method of treating chronic obstructive pulmonary disease or asthma, the method comprising administering to a patient a therapeutically effective amount of a compound of claim 1 .