Muscarinic acetylcholine receptor antagonists

1. 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;

m is an integer having a value of 1 to 15;

X, Y, Z, and W are independently selected from the group consisting of hydrogen and —C1-4 alkyl;

X − is a pharmaceutically acceptable anion selected from the group consisting of chloride, bromide, iodide, hydroxide, sulfate, nitrate, phosphate, acetate, trifluoroacetate, fumarate, citrate, tartrate, oxalate, succinate, mandelate, methanesulfonate, and p-toluenesulfonate.

2. A compound according to claim 1 wherein X, Y, Z, and W are hydrogen.

3. The compound according to claim 2 which is:

1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane bromide; or

1-[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propyl]-4˜[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane bromide.

4. A compound of formula (I)

wherein:

R1 is selected from the group consisting of —C1-15 alkyl, halosubstituted —C1-15 alkyl, —C1-15alkyl cycloalkyl, —C2-15 alkenyl, hydroxyl substituted —C1-15 alkyl, —C1-15 alkylaryl, —C1-15 alkyl heteroaryl, —(CR7R7)qNRaRa, —(CR7R7)qNC(O)Ra, —(CR7R7)qNC(O)NRaRa, —(CR7R7)qC(O)Ra, —(CR7R7)qOC(O)Ra, —(CR7R7)qORc, and —(CR7R7)qNS(O) 2 Ra;

R2 and R3 are independently selected from the group consisting of:

wherein 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;

R7 is selected from a group consisting of hydrogen, —C1-4 alkyl, halosubstituted —C1-4 alkyl, and hydroxysubstituted —C1-4 alkyl;

Ra is selected from the group consisting of hydrogen, —C1-15 alkyl, —C1-15 alkoxy, aryl, —C1-15 alkyl aryl, heteroaryl, —C1-15 alkyl heteroaryl, heterocyclic, and a —C1-15 alkyl heterocyclic moiety, all of which moieties excluding hydrogen may be optionally substituted;

Rc is selected from a group consisting of hydrogen, —C1-15 alkyl, —C1-15 alkoxy, heterocyclic, and a —C1-15 alkyl heterocyclic moiety, all of which moieties, excluding hydrogen may be optionally substituted;

q is 0 or an integer having a value of 1 to 15;

X − is a pharmaceutically acceptable anion selected from the group consisting of chloride, bromide, iodide, hydroxide, sulfate, nitrate, phosphate, acetate, trifluoroacetate, fumarate, citrate, tartrate, oxalate, succinate, mandelate, methanesulfonate, and p-toluenesulfonate.

5. The compound according to claim 4 wherein R1 is —C1-15 alkyl.

6. The compound according to claim 5 which is:

1-ethyl-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane bromide;

4-[hydroxy(diphenyl)methyl]-1-nonyl-1-azoniabicyclo[2.2.2]octane bromide;

4-[hydroxy(diphenyl)methyl]-1-methyl-1-azoniabicyclo[2.2.2]octane bromide;

1-butyl-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane bromide;

1-hexyl-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane bromide;

4-[hydroxy(diphenyl)methyl]-1-propyl-1-azoniabicyclo[2.2.2]octane bromide; or

1-butyl-4-[hydroxy(di-3-thienyl)methyl]-1-azoniabicyclo[2.2.2]octane bromide.

7. The compound according to claim 4 wherein R1 is halosubstituted —C1-15 alkyl.

8. The compound according to claim 7 which is:

1-(3-bromopropyl)-4-hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane bromide.

9. The compound according to claim 4 wherein R1 is —C1-15 alkyl cycloalkyl.

10. The compound according to claim 9 which is:

1-(cyclopropylmethyl)-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane bromide.

11. The compound according to claim 4 wherein R1 is —C2-15 alkenyl.

12. The compound according to claim 11 which is:

4-[hydroxy(diphenyl)methyl]-1-(4-penten-1-yl)-1-azoniabicyclo[2.2.2]octane bromide;

4-[hydroxy(diphenyl)methyl]-1-(2-propen-1-yl)-1-azoniabicyclo[2.2.2]octane bromide; or

1-(5-hexen-1-yl)-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane bromide.

13. The compound according to claim 4 wherein R1 is hydroxyl substituted —C1-15 alkyl.

14. The compound according to claim 13 which is:

4-[hydroxy(diphenyl)methyl]-1-(2-hydroxyethyl)-1-azoniabicyclo[2.2.2]octane bromide.

15. The compound according to claim 4 wherein R1 is —C1-15 alkyl aryl.

16. The compound according to claim 15 which is:

4-[hydroxy(diphenyl)methyl]-1-(2-phenylethyl)-1-azoniabicyclo[2.2.2]octane bromide;

4-[hydroxy(diphenyl)methyl]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane bromide;

4-[hydroxy(diphenyl)methyl]-1-(1-phenylmethyl)-1-azoniabicyclo[2.2.2]octane bromide

4-[hydroxy(diphenyl)methyl]-1-(2-naphthylmethyl)-1-azoniabicyclo[2.2.2]octane bromide;

4-[hydroxy(di-2-thienyl)methyl]-1-(2-phenylethyl)-1-azoniabicyclo[2.2.2]octane bromide; or

4-[hydroxy(di-2-thienyl)methyl]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane bromide.

17. The compound according to claim 4 wherein R1 is —C1-15 alkyl heteroaryl.

18. The compound according to claim 17 which is:

4-[hydroxy(diphenyl)methyl]-1-[2-(1H-indol-3-yl)ethyl]-naphthylmethyl)-1-azoniabicyclo[2.2.2]octane bromide.

19. The compound according to claim 4 wherein R1 is —(CR7R7)qNRaRa.

20. The compound according to claim 19 which is:

1-(2-aminoethyl)-1-azoniabicyclo[2.2.2]oct-4-yl](diphenyl)methanolate trifluoroacetate.

21. The compound according to claim 4 wherein R1 is —(CR7R7)qC(O)Ra.

22. The compound according to claim 21 which is:

4-[hydroxy(diphenyl)methyl]-1-(2-oxo-2-phenylethyl)-1-azoniabicyclo[2.2.2]octane-bromide;

1-[2-(1-benzofuran-2-yl)-2-oxoethyl]-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]-octane bromide;

1-[2-([1,1′-biphenyl]-4-yl)-2-oxoethyl]-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]-octane bromide; or

1-[2-(naphthalen-2-yl)-2-oxoethyl]-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2 ]-octane bromide.

23. The compound according to claim 4 wherein R1 is —(CR7R7)qOC(O)Ra.

24. The compound according to claim 23 which is:

1-[2-(benzoyloxy)ethyl]-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane-bromide.

25. The compound according to claim 4 wherein R1 is —(CR7R7)qORc.

26. The compound according to claim 25 which is:

4-[hydroxy(diphenyl)methyl]-1-[2-(methyloxy)ethyl]-1-azoniabicyclo[2.2.2]octane bromide; or

4-[hydroxy(diphenyl)methyl]-1-[3-(methyloxy)propyl]-1-azoniabicyclo[2.2.2]octane bromide.

27. A pharmaceutical composition comprising a compound according to claim 1 , and a pharmaceutically acceptable carrier thereof.

28. A pharmaceutical composition comprising a compound according to claim 4 , and a pharmaceutically acceptable carrier thereof.

29. A pharmaceutical composition according to claim 1 in a form suitable for administration by oral or nasal inhalation.

30. A pharmaceutical composition according to claim 4 in a form suitable for administration by oral or nasal inhalation.