Diamide compounds having muscarinic receptor antagonist and β2 adrenergic receptor agonist activity
The invention relates to a pharmaceutical composition comprising an isotonic aqueous solution comprising a compound of formula I: or a pharmaceutically acceptable salt thereof.
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):
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;
R a is selected from C 1-6 alkyl;
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.
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. 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.
21. 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.
22. 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.