Muscarinic acetylcholine receptor antagonists
Muscarinic Acetylcholine Receptor Antagonists and methods of using them are provided.
1. A method of inhibiting the binding of acetylcholine to an acetylcholine receptor in a human in need thereof, which comprises contacting the acetylcholine receptor with an effective amount of a compound of Formula (I)
wherein:
R1 is
R2 and R3 are independently selected from the group consisting of:
where F, G, H, K, and L are independently selected from the group consisting of hydrogen, halogen, —C1-4 alkyl, halosubstituted —C1-4 alkyl, hydroxyl substituted alkyl, and —C1-4 alkoxy;
l is an integer having a value of 1 or 2;
n is an integer having a value of 1 to 4;
M is O or CH 2 ;
V is O or CH 2 ;
X − is a pharmaceutically acceptable anion, and
wherein the method of contacting the receptor is by topical application to said human.
2. The method according to claim 1 wherein the pharmaceutically acceptable anion is chloride, bromide, iodide, hydroxide, sulfate, nitrate, phosphate, acetate, trifluoroacetate, fumarate, citrate, tartrate, oxalate, succinate, mandelate, methanesulfonate or p-toluenesulfonate.
3. The method according to claim 1 wherein M is O.
4. The method according to claim 3 wherein n is 2.
5. The method according to claim 4 wherein l is 2.
6. The method according to claim 1 wherein V is CH 2 .
7. The method according to claim 1 wherein V is O.
8. The method according to claim 1 wherein M is CH 2 .
9. The method according to claim 1 wherein l is 1.
10. The method according to claim 1 wherein l is 2.
11. The method according to claim 2 wherein one of R2 and R3 is:
12. The method according to claim 2 wherein both R2 and R3 are independently selected from:
13. The method according to claim 2 wherein one of R2 and R3 is:
14. The method according to claim 2 wherein one of R2 and R3 is:
15. The method according to claim 1 which is:
4-[hydroxy(diphenyl)methyl]-1-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1-azoniabicyclo[2.2.2]octane bromide.
16. The method according to claim 1 wherein the topical contact of the acetylcholine receptor is in the respiratory tract of said human.
17. The method according to claim 16 wherein the method of contact of the acetylcholine receptor is via inhalation by the mouth or nose of said human.
18. The method according to claim 16 wherein the method of contacting the receptor is via the mouth.
19. The method according to claim 16 wherein the method of contacting the receptor is via the nose.
20. The method according to claim 16 wherein the method of contacting is by administration of the compound from a medicament dispenser selected from a reservoir dry powder inhaler, a multi-dose dry powder inhaler or a metered dose inhaler.
21. The method according to claim 1 wherein the inhibition of the binding of acetylcholine to an acetylcholine receptor is useful in the treatment of chronic obstructive lung disease, chronic bronchitis, asthma, chronic respiratory obstruction, pulmonary fibrosis, pulmonary emphysema, or allergic rhinitis.
22. The method according to claim 1 wherein the inhibition of the binding of acetylcholine to an acetylcholine receptor is useful in the treatment of chronic obstructive lung disease.
23. The method according to claim 1 wherein the inhibition of the binding of acetylcholine to an acetylcholine receptor is useful in the treatment of asthma.
24. The method according to claim 1 wherein the inhibition of the binding of acetylcholine to an acetylcholine receptor is useful in the treatment of chronic respiratory obstruction.
25. The method according to claim 1 wherein the inhibition of the binding of acetylcholine to an acetylcholine receptor is useful in the treatment of pulmonary emphysema.
26. The method according to claim 1 wherein the inhibition of the binding of acetylcholine to an acetylcholine receptor is useful in the treatment of allergic rhinitis.