Diamide Compounds Having Muscarinic Receptor Antagonist and Beta2 Adrenergic Receptor Agonist Activity

1 . A method of treating a pulmonary disorder in a patient, comprising administering a pharmaceutical composition comprising an isotonic aqueous solution comprising a compound of formula I:

wherein

Y is a group of formula (a):

Ar 1  n CH 2  p XCH 2  q   (a)

and Y is attached at the 3- or 4-position of the phenylene ring relative to the —CH 2 —(CR 5 R 6 ) e — group;

X is selected from —C(O)NH— and —NHC(O)—;

Ar 1 is selected from phen-1,3-ylene and phen-1,4-ylene, wherein the phenylene group is unsubstituted or substituted with 1 to 3 substituents selected independently from C 1-3 alkyl, —O—(C 1-3 alkyl) and halo;

each R 1 is selected independently from C 1-3 alkyl, —O—(C 1-3 alkyl), hydroxyl and halo;

each R 2 is selected independently from C 1-3 alkyl, —O—(C 1-3 alkyl) and halo;

each R 3 is selected independently from C 1-3 alkyl; or two R 3 groups are joined to form C 1-3 alkylene, C 2-3 alkenylene or oxiran-2,3-diyl;

each R 4 is selected independently from C 1-3 alkyl, —O—(C 1-3 alkyl) and halo;

R 5 is selected from hydrogen, methyl and ethyl;

R 6 is selected from hydrogen, methyl and ethyl;

a is 0, 1, 2 or 3;

b is 0, 1, 2 or 3;

c is 0, 1, 2, 3 or 4;

d is 0, 1, 2 or 3;

e is 0 or 1;

n is 0 or 1;

p is 0, 1, 2, 3, 4, 5 or 6; provided that when n is 0, p is 1, 2, 3, 4, 5 or 6;

q is 0, 1, 2, 3, 4, 5 or 6;

or a pharmaceutically acceptable salt thereof,

wherein the pulmonary disorder is asthma or chronic obstructive pulmonary disorder.

2 . The method of claim 1 , wherein Y is —(CH 2 ) p —X—.

3 . The method of claim 1 , wherein Y is —(CH 2 ) p —X—(CH 2 ) q —.

4 . The method of claim 1 , wherein Y is —Ar 1 —(CH 2 ) p —X—(CH 2 ) q —.

5 . The method of claim 1 , wherein Y is —Ar 1 —X—.

6 . The method of claim 1 , wherein R 5 is hydrogen or methyl; and R 6 is hydrogen.

7 . The method of claim 1 , wherein R a is methyl.

8 . The method of claim 1 , wherein each R 4 is independently selected from methyl, methoxy, chloro and fluoro.

9 . The method of claim 1 , wherein a, b and c are 0.

10 . The method of claim 1 , wherein the compound has formula II:

or a pharmaceutically acceptable salt thereof.

11 . The method of claim 10 , wherein each R 4 is selected independently from methyl, methoxy, chloro and fluoro;

R a is methyl;

d is 0, 1 or 2; and

p is 3 or 4.

12 . The method of claim 10 , wherein each R 4 is selected independently from methyl, methoxy, chloro and fluoro;

R a is methyl;

d is 0, 1 or 2; and

p is 4.

13 . The method of claim 1 , wherein the compound has formula III:

or a pharmaceutically acceptable salt thereof.

14 . The method of claim 13 , wherein

R 5 is methyl;

R a is methyl;

p is 3 or 4; and

q is 1.

15 . The method of claim 1 , wherein the compound has formula IV:

or a pharmaceutically acceptable salt thereof.

16 . The method of claim 15 , wherein

R 4 is selected from methyl, methoxy, and fluoro;

R 5 is hydrogen or methyl;

R a is methyl;

d is 0 or 1;

p is 1; and

q is 1 or 2.

17 . The method of claim 1 , wherein the compound has formula V:

or a pharmaceutically acceptable salt thereof.

18 . The method of claim 17 , wherein each R 4 is selected independently from methyl, methoxy, chloro and fluoro;

R 5 is hydrogen or methyl;

R a is methyl; and

d is 0, 1 or 2.

19 . The method of claim 1 , wherein the compound is biphenyl-2-ylcarbamic acid 1-[2-({3-[2-(3-{(S)-2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]propyl}phenyl)acetylamino]-propyl}methylcarbamoyl)-ethyl]piperidin-4-yl ester or a pharmaceutically acceptable salt thereof.

20 . (canceled)

21 . The method of claim 1 , wherein the compound is biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-2,5-dimethylphenylcarbamoyl)butyl]methylcarbamoyl}ethyl)-piperidin-4-yl ester or a pharmaceutically acceptable salt thereof.

22 . The method of claim 1 , wherein the compound is biphenyl-2-ylcarbamic acid 1-(2-{[3-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]ethyl}phenylcarbamoyl)phenyl]methylcarbamoyl}ethyl)piperidin-4-yl ester or a pharmaceutically acceptable salt thereof.

23 . The method of claim 1 , wherein the compound is biphenyl-2-ylcarbamic acid 1-{2-[(4-{[2-(3-{(R)-2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]propyl}phenyl)ethylcarbamoyl]methyl}phenyl)-methylcarbamoyl]ethyl}piperidin-4-yl ester or a pharmaceutically acceptable salt thereof.

24 . (canceled)

25 . The method of claim 1 , wherein the composition comprises a further therapeutic agent.

26 . The pharmaceutical composition of claim 1 , wherein the therapeutic agent is a steroidal anti-inflammatory agent or a pharmaceutically acceptable salt or solvate thereof.

27 . The pharmaceutical composition of claim 1 , wherein the steroidal anti-inflammatory agent is a corticosteroid or a pharmaceutically acceptable salt or solvate thereof.

28 - 35 . (canceled)