Biphenyl compounds useful as muscarinic receptor antagonists

1. A compound of formula I:

wherein:

a is 0 or an integer of from 1 to 5;

each R 1 is independently selected from (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (3-6C)cycloalkyl, cyano, halo, —OR 1a , —C(O)OR 1b , —SR 1c , —S(O)R 1d , —S(O) 2 R 1e , —NR 1f R 1g , —NR 1h S(O) 2 R 1i , and —NR 1j C(O)R 1k ; where each of R 1a , R 1b , R 1c , R 1d , R 1e , R 1f , R 1g , R 1h , R 1i , R 1j , and R 1k is independently hydrogen, (1-4C)alkyl or phenyl(1-4C)alkyl;

b is 0 or an integer of from 1 to 4;

each R 2 is independently selected from (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (3-6C)cycloalkyl, cyano, halo, —OR 2a , —C(O)OR 2b , —SR 2c , —S(O)R 2d , —S(O) 2 R 2e , —NR 2f R 2g , —NR 2h S(O) 2 R 2i , and NR 2j C(O)R 2k ; where each of R 2a , R 2b , R 2c , R 2d , R 2e , R 2f , R 2g , R 2h , R 2i , R 2j , and R 2k is independently hydrogen, (1-4C)alkyl or phenyl(1-4C)alkyl;

W represents O or NW a , where W a is hydrogen or (1-4C)alkyl;

c is 0 or an integer from 1 to 5;

each R 3 independently represents (1-4C)alkyl or two R 3 groups are joined to form (1-3C)alkylene, (2-3C)alkenylene or oxiran-2,3-diyl;

m is 0 or 1;

R 4 is selected from hydrogen, (1-4C)alkyl, and (3-4C)cycloalkyl;

s is 0, 1 or 2;

Ar 1 represents phen-1,3-ylene, phen-1,4-ylene, 2,4-thienylene, 2,5-thienylene, 2,5-furylene, 2,5-pyridylene, 2,6-pyridylene, or 2,5-pyrrolylene; wherein the phenylene, thienylene, furylene, pyridylene or pyrrolylene group is optionally substituted with 1 or 2 R5 substituents and each R 5 is selected independently from halo, hydroxy, (1-4C)alkyl or (1-4)alkoxy;

t is 0, 1 or 2;

p is 0, 1 or 2;

each R 6 independently represents (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (3-6C)cycloalkyl, cyano, nitro, halo, N,N-di(1-4C)alkylamino(2-4C)alkoxy, —OR 6a , —C(O)OR 6b , —SR 6c , —S(O)R 6d , —S(O) 2 R 6e or NR 6f R 6g ; each of R 6a , R 6b , R 6c , R 6d , R 6e , R 6f and R 6g is independently hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl, phenyl or phenyl(1-4C)alkyl, wherein each phenyl group is unsubstituted or substituted by 1 or 2 substituents selected independently from halo, (1-4C)alkyl and (1-4C)alkoxy; and

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 are independently selected from hydrogen and (1-4alkyl);

R 7 is selected from hydrogen, (1-4C)alkyl, (3-4C)cycloalkyl, —C(O)(1-4C)alkyl, -(1-4C)alkyleneC(O)OR 7a , —C(O)heterocyclyl, —C(O)CH(NH 2 )(1-4C)alkyleneQ, -(1-4C)alkyleneC(O)Z, —C(O)(1-4C)alkyleneZ, and —S(O) 2 (1-4C)alkyleneZ; where Q is a nitrogen-containing substituent selected from —NR 7b R 7c and heteroaryl; Z is a nitrogen-containing substituent selected from —NR 7d R 7e and heterocyclyl; R 7a is hydrogen or (1-4C)alkyl; each of R 7b , R 7c , R 7d and R 7e independently represents hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl or hydroxyphenyl, and where (1-4C)alkyl is unsubstituted or substituted by 1 or 2 substituents selected independently from amido, cyano, furyl, hydroxyl, and methylimidazolyl; the heterocyclyl contains 1 or 2 nitrogen atoms, and is unsubstituted or substituted by 1 or 2 substituents selected independently from hydroxyl, amido, (1-4C)alkoxy, oxo, —S(O) 2 (1-4C)alkyl, —(CH 2 )O(1-4C)alkyl, -(1-4C)alkyleneOH, —NR 7f R 7g or —C(O)NR 7h R 7i , where each of R 7f , R 7g , R 7h and R 7i independently represents hydrogen or (1-4C)alkyl; and the heteroaryl contains 1 or 2 nitrogen atoms;

wherein each alkyl and alkoxy group in R 1 , R 1a-1k , R 2 , R 2a-2k , R 3 , R 6 , and R 6a-6g is optionally substituted with 1 to 5 fluoro substituents;

or a pharmaceutically acceptable salt or solvate or stereoisomer thereof.

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

3. The compound of claim 1 , wherein W represents O.

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

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

6. The compound of claim 1 wherein q is 1 and R 5 is selected from halo and (1-4C)alkoxy.

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

8. The compound of claim 1 , wherein p is 0.

9. The compound of any one of claims 1 to 8 , wherein R 4 is hydrogen or methyl.

10. The compound of any one of claims 1 to 8 , wherein R 7 is hydrogen or methyl.

11. A compound selected from:

biphenyl-2-ylcarbamic acid 1-[2-({4-[(4-hydroxybenzylamino)methyl]benzoyl}methylamino)ethyl]piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-{2-[(4-{[2-(4-hydroxyphenyl)ethylamino]methyl}benzoyl)methylamino]ethyl}piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-(2-{4-[(4-hydroxybenzylamino)methyl]benzoylamino}ethyl)piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-[2-({4-[(3-hydroxybenzylamino)methyl]benzoyl}methylamino)ethyl]piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-[2-(4-{[2-(4-hydroxyphenyl)ethylamino]methyl}benzoylamino) ethyl]piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-[2-(4-{[(4-hydroxybenzyl)methylamino]methyl}benzoylamino) ethyl]piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-{2-[4-({[2-(4-hydroxyphenyl)ethyl]methylamino}methyl) benzoyamino]ethyl}piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-[2-(2-fluoro-4-{[2-(4-hydroxyphenyl)ethylamino]methyl}benzoylamino)ethyl]piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-{2-[(2-fluoro-4-{[2-(4-hydroxyphenyl)ethylamino]methyl≡benzoyl)methylamino]ethyl}piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-[2-(4-{[2-(4-hydroxyphenyl)ethylamino]methyl}-2-methoxybenzoyl)methylamino]ethyl}piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-{2-[(4-{[2-(4-hydroxyphenyl)ethylamino]methyl}-2-methooxybenzoyl)methylamino]ethyl}piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-{2-[(5-{[2-(4-hydroxyphenyl)ethylamino]methyl}thiophene-2-carbonyl)methylamino]ethyl}piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-{2-[(5-{[2-(4-hydroxyphenyl)ethylamino]methyl}thiophene-2-carbonyl)amino]ethyl}piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-{2-[(5-{[2-(4-hydroxyphenyl)ethylamino]methyl}furan-2-carbonyl)methylamino]ethyl}piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-{2-[(5-{[2-(4-hydroxyphenyl)ethylamino]methyl}furan-2-carbonyl)amino]ethyl}piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-{2-[(5-{[2-(4-hydroxyphenyl)ethylamino]methyl}pyridine-2-carbonyl)methylamino]ethyl}piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-{2-[(5-{[2-(4-hydroxyphenyl)ethylamino]methyl}-1H-pyrrole-2-carbonyl)methylamino]ethyl}piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-[2-({5-[(4-hydroxybenzylamino)methyl]thiophene-2-carbonyl}methylamino)ethyl]piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-[2-({5-[(4-hydroxybenzylamino)methyl]thiophene-2-carbonyl}amino)ethyl]piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-[2-({5-[(4-hydroxybenzylamino)methyl]-1H-pyrrole-2-carbonyl}methylamino)ethyl]piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-[2-({5-[(4-hydroxybenzylamino)methyl]furan-2-carbonyl}methylamino)ethyl]piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-[2-({5-[(4-hydroxybenzylamino)methyl]furan-2-carbonyl}amino)ethyl]piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-{2-[2-(4-{[2-(4-hydroxyphenyl)ethylamino]methyl}phenyl)acetylamino]ethyl}piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-{2-[3-(4-{[2-(4-hydroxyphenyl)ethylamino]methyl}phenyl)propionylamino]ethyl}piperidin-4-yl ester;

biphenyl-2-yl-carbamic acid 1-[2-(3-{4-[(4-hydroxybenzylamino)methyl]phenyl}propionylamino) ethyl]piperidin-4-yl ester;

biphenyl-2-yl-carbamic acid 1-{2-[(3-{4-[(4-hydroxybenzylamino)methyl]phenyl}propionyl) methylamino]ethyl}piperidin-4-yl ester;

biphenyl-2-yl-carbamic acid 1-{2-[(3-{4-[(3-hydroxybenzylamino)methyl]phenyl}propionyl) methylamino]ethyl}piperidin-4-yl ester;

or a pharmaceutically acceptable salt or solvate thereof.

12. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 1 or 11 .

13. The pharmaceutical composition of claim 12 , 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.

14. The pharmaceutical composition of claim 13 , wherein the composition comprises a therapeutically effective amount of a β 2 adrenergic receptor agonist and a steroidal anti-inflammatory agent.

15. A process for preparing a compound as claimed in claim 1 or 11 , 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.

16. The process of claim 15 , wherein the process further comprises forming a pharmaceutically acceptable salt of the compound of formula I.

17. The product prepared by the process of claim 15 .

18. The product prepared by the process of claim 16 .

19. 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 or 11 .

20. 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 or 11 .