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Details for Patent: 8,575,347

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Details for Patent: 8,575,347

Title:Muscarinic acetylcholine receptor antagonists
Abstract: Muscarinic Acetylcholine Receptor Antagonists and methods of using them are provided.
Inventor(s): Laine; Dramane Ibrahim (King of Prussia, PA), Palovich; Michael R. (King of Prussia, PA), McCleland; Brent W. (King of Prussia, PA), Neipp; Christopher E. (King of Prussia, PA), Thomas; Sonia M. (King of Prussia, PA)
Assignee: Glaxo Group Limited (Greenford, Middlesex, GB)
Filing Date:Sep 26, 2012
Application Number:13/627,007
Claims:1. A compound of formula (I) ##STR00047## wherein: R1 is ##STR00048## R2 and R3 are independently selected from the group consisting of: ##STR00049## 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.sup.- 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)m- ethyl]-1-azoniabicyclo[2.2.2]octane bromide; or 1-[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propyl]-4.about.[hydroxy(dip- henyl)methyl]-1-azoniabicyclo[2.2.2]octane bromide.

4. A compound of formula (I) ##STR00050## 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).sub.2Ra; R2 and R3 are independently selected from the group consisting of: ##STR00051## 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.sup.- 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]octan- e 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]o- ctane 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]octan- e 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]octa- ne 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]octan- e 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]octa- ne bromide 4-[hydroxy(diphenyl)methyl]-1-(2-naphthylmethyl)-1-azoniabicycl- o[2.2.2]octane bromide; 4-[hydroxy(di-2-thienyl)methyl]-1-(2-phenylethyl)-1-azoniabicyclo[2.2.2]o- ctane 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-azonia- bicyclo[2.2.2]-octane bromide; 1-[2-([1,1'-biphenyl]-4-yl)-2-oxoethyl]-4-[hydroxy(diphenyl)methyl]-1-azo- niabicyclo[2.2.2]-octane bromide; or 1-[2-(naphthalen-2-yl)-2-oxoethyl]-4-[hydroxy(diphenyl)methyl]-1-azoniabi- cyclo[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.
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