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
F, G, H, K and L are independently selected from the group consisting of hydrogen, halogen, C 1-4 alkyl, halosubstituted C 1-4 alkyl, hydroxy substituted alkyl, and C 1-4 alkoxy;
R4 and R5 are independently selected from the group consisting of hydrogen, halogen, C1-4 alkyl, aryl, —C1-4 alkyl aryl, cyano, nitro, —(CR7R7)pORb and (CR7R7)pNRbRb;
R6 is selected from the group consisting of hydrogen, C1-4 alkyl;
m is an integer having a value of 1 to 15;
t is 0 or an integer having a value of 1 to 5;
p is 0 or an integer having a value of 1 to 4;
Rb is selected from the group consisting of hydrogen, —C1-4 alkyl, aryl and —C1-4 alkyl aryl;
R7 is selected from the group consisting of hydrogen, C1-4 alkyl, halosubstituted C1-4 alkyl, and hydroxy substituted C1-4 alkyl; and
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 2 wherein the pharmaceutically acceptable anion is bromide.
4. The method according to claim 2 wherein the pharmaceutically acceptable anion is iodide.
5. The method according to claim 1 wherein
m is an integer having a value of 1 to 5;
t is 0, 1 or 2;
p is 0, 1 or 2;
R6 is selected from the group consisting of hydrogen and C1-4 alkyl;
Rb is selected from the group consisting of hydrogen, and C1-4 alkyl; and
R7 is selected from the group consisting of hydrogen and C1-4 alkyl.
6. The method according to claim 1 wherein R2 and R3 are both independently selected from
7. The method according to claim 6 wherein F, G, H, K and L are hydrogen.
8. The method according to claim 1 wherein R2 and R3 are both independently selected from
9. The method according to claim 8 wherein F, G and H are hydrogen.
10. The method according to claim 1 wherein R4 and R5 are both hydrogen.
11. The method according to claim 1 wherein m is 2, 3 or 4.
12. The method according to claim 1 wherein t is 0 or 1.
13. The method according to claim 1 wherein m is 2 and t is 1.
14. The method according to claim 1 wherein R2 and R3 are both phenyl, R4 and R5 are both hydrogen, m is 2 and t is 1.
15. The method according to claim 1 wherein R6 is hydrogen.
16. The method according to claim 1 wherein F, G, H, K and L are independently selected from the group consisting of hydrogen, halogen, methyl and or methoxy.
17. The method according to claim 1 wherein p is 0.
18. The method according to claim 1 wherein R7 is hydrogen.
19. The method according to claim 1 wherein the topical contact of the acetylcholine receptor is in the respiratory tract of said human.
20. The method according to claim 19 wherein the method of contact of the acetylcholine receptor is via inhalation by the mouth or nose of said human.
21. A method of inhibiting the binding of acetylcholine to a M 3 muscarinic acetylcholine receptor in a human in need thereof, which comprises contacting the M 3 muscarinic 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
F, G, H, K and L are independently selected from the group consisting of hydrogen, halogen, C 1-4 alkyl, halosubstituted C 1-4 alkyl, hydroxy substituted alkyl, and C 1-4 alkoxy;
R4 and R5 are independently selected from the group consisting of hydrogen, halogen, C1-4 alkyl, aryl, —C1-4 alkyl aryl, cyano, nitro, —(CR7R7)pORb and —(CR7R7)pNRbRb;
R6 is selected from the group consisting of hydrogen, C1-4 alkyl;
m is an integer having a value of 1 to 15;
t is 0 or an integer having a value of 1 to 5;
p is 0 or an integer having a value of 1 to 4;
Rb is selected from the group consisting of hydrogen, C1-4 alkyl, aryl and —C1-4 alkyl aryl;
R7 is selected from the group consisting of hydrogen, C1-4 alkyl, halosubstituted C1-4 alkyl, and hydroxy substituted C1-4 alkyl; and
X − is a pharmaceutically acceptable anion, and wherein the method of contacting the receptor is by topical application to said human.
22. The method according to claim 21 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.
23. The method according to claim 22 wherein the pharmaceutically acceptable anion is bromide.
24. The method according to claim 22 wherein the pharmaceutically acceptable anion is iodide.
25. The method according to claim 21 wherein the binding of acetylcholine to a M 3 muscarinic acetylcholine receptor is in the respiratory tract of said human.
26. The method according to claim 21 wherein the binding of acetylcholine to a M 3 muscarinic acetylcholine receptor is by topical delivery to said human.
27. The method according to claim 21 wherein the topical contact of the M 3 muscarinic acetylcholine receptor is in the respiratory tract of said human.
28. The method according to claim 27 wherein the method of contact of the M 3 muscarinic acetylcholine receptor is via inhalation by the mouth or nose of said human.
29. The method according to claim 28 wherein the method of contacting the receptor is via the mouth.
30. The method according to claim 28 wherein the method of contacting the receptor is via the nose.
31. The method according to claim 28 wherein the method of contacting by inhalation is via 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.
32. The method according to claim 21 wherein the inhibition of the binding of acetylcholine to a M 3 muscarinic 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.
33. The method according to claim 20 wherein the method of contacting the receptor is via the mouth.
34. The method according to claim 20 wherein the method of contacting the receptor is via the nose.
35. The method according to claim 19 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.
36. 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.
37. The method according to claim 36 wherein the treatment is for chronic obstructive lung disease.
38. The method according to claim 36 wherein the treatment is for asthma.
39. The method according to claim 36 wherein the treatment is for chronic respiratory obstruction.
40. The method according to claim 36 wherein the treatment is for pulmonary emphysema.
41. The method according to claim 36 wherein the treatment is for allergic rhinitis.
42. The method according to claim 21 wherein the pharmaceutically acceptable anion is iodide.
43. The method according to claim 21 wherein
m is an integer having a value of 1 to 5;
t is 0, 1 or 2;
p is 0, 1 or 2;
R6 is selected from the group consisting of hydrogen and C1-4 alkyl;
Rb is selected from the group consisting of hydrogen, and C1-4 alkyl; and
R7 is selected from the group consisting of hydrogen and C1-4 alkyl.
44. The method according to claim 21 wherein R2 and R3 are both independently selected from
45. The method according to claim 44 wherein F, G, H, K and L are hydrogen.
46. The method according to claim 21 wherein R2 and R3 are both independently selected from
47. The method according to claim 8 wherein F, G and H are hydrogen.
48. The method according to claim 21 wherein R4 and R5 are both hydrogen.
49. The method according to claim 21 wherein m is 2, 3 or 4; and t is 0 or 1.
50. The method according to claim 21 wherein m is 2 and t is 1.
51. The method according to claim 21 wherein R2 and R3 are both phenyl, R4 and R5 are both hydrogen, m is 2 and t is 1.
52. The method according to claim 21 wherein R6 is hydrogen.
53. The method according to claim 21 wherein F, G, H, K and L are independently selected from the group consisting of hydrogen, halogen, methyl and or methoxy.
54. The method according to claim 21 wherein p is 0.
55. The method according to claim 21 wherein R7 is hydrogen.