1,3-dioxanomorphides and 1,3-dioxanocodides

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

G is R 1 or a hydroxyl protecting group PG;

R 1 is hydrogen, C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl(C 1-4 )alkyl, or C 6-10 aryl (C 1-4 )alkyl, wherein the C 3-6 cycloalkyl, and C 6-10 aryl, portions thereof are optionally substituted with 1, 2, or 3 substituents, each independently selected from the group consisting of hydroxy, halo, halo(C 1-4 )alkyl, amino, C 1-4 alkylamino, di(C 1-4 )alkylamino, carboxy, and C 1-4 alkoxycarbonyl;

PG is selected from the group consisting of methyl, tert-butyl, benzyl, benzovl, acetyl, trimethyl silyl, tert-butyldimethyl silyl, tert-butyldiphenyl silyl, and tri-isopropyl silyl;

R 2 is

(a) hydrogen; or

(b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl(C 1-4 )alkyl, C 3-7 cycloalkenyl(C 1-4 )alkyl, or C 6-10 aryl(C 1-4 )alkyl, any of which is optionally substituted with 1, 2, or 3 substituents, each independently selected from the group consisting of hydroxy, halo, halo(C 1-4 )alkyl, amino, C 1-4 alkylamino, di(C 1-4 )alkylamino, carboxy, and C 1-4 alkoxycarbonyl;

R 3 and R 4 are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, wherein any of which, when other than hydrogen, is optionally substituted with 1, 2, or 3 substituents, each independently selected from the group consisting of hydroxy, halo, halo(C 1-4 )alkyl, amino, C 1-4 alkylamino, di(C 1-4 )alkylamino, carboxy, and C 1-4 alkoxycarbonyl;

R 5 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, phenyl, and naphthyl wherein any of which, when other than hydrogen, is optionally substituted with 1, 2, or 3 substituents, each independently selected from the group consisting of hydroxy, halo, halo(C 1-4 )alkyl, amino, C 1-4 alkylamino, di(C 1-4 )alkylamino, carboxy, and C 1-4 alkoxycarbonyl; and

is a single bond or a double bond.

2. The compound of claim 1 , having the Formula II:

or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein

R 3 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, wherein any of which, when other than hydrogen, is optionally substituted with 1, 2, or 3 substituents, each independently selected from the group consisting of hydroxy, halo, halo(C 1-4 alkyl, amino, C 1-4 alkylamino, di(C 1-4 )alkylamino, carboxy, and C 1-4 alkoxycarbonyl;

R 4 is selected from the group consisting of hydrogen, C 1-6 alkyl,C 2-6 alkenyl, and C 2-6 alkenyl, wherein any of which, when other than hydrogen, is optionally substituted with 1, 2, or 3 substituents, each independently selected from the group consisting of hydroxy, halo, halo(C 1-4 )alkyl, amino, C 1-4 alkylamino, di(C 1-4 )alkylamino, carboxy, and C 1-4 alkoxycarbonyl; and

G, R 1 , R 2 , R 5 and are as defined in claim 1 .

3. The compound of claim 1 , having the Formula III:

or a pharmaceutically acceptable salt thereof, wherein

R 3 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, wherein any of which, when other than hydrogen, is optionally substituted with 1, 2, or 3 substituents, each independently selected from the group consisting of hydroxy, halo, halo(C 1-4 )alkyl, amino, C 1-4 alkylamino, di(C 1-4 )alkylamino, carboxy, and C 1-4 alkoxycarbonyl;

R 4 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkenyl, wherein any of which, when other than hydrogen, is optionally substituted with 1, 2, or 3 substituents, each independently selected from the group consisting of hydroxy, halo, halo(C 1-4 )alkyl, amino, C 1-4 alkylamino, di(C 1-4 )alkylamino, carboxy, and C 1-4 alkoxycarbonyl; and

G, R 1 , R 2 , R 5 and are as defined in claim 1 .

4. The compound of claim 1 , having the Formula IV:

or a pharmaceutically acceptable salt thereof, wherein G, R 1 -R 5 and are as defined in claim 1 .

5. The compound of claim 2 , having the Formula V:

or a pharmaceutically acceptable salt, thereof, wherein G, R 1 -R 5 and are as defined in claim 2 .

6. The compound of claim 3 , having the Formula VI:

or a pharmaceutically acceptable salt, thereof, wherein G, R 1 -R 5 and are as defined in claim 3 .

7. The compound of claim 1 , having the Formula VII:

or a pharmaceutically acceptable salt thereof, wherein G, R 1 -R 5 and are as defined in claim 1 .

8. The compound of claim 2 , having the Formula VIII:

or a pharmaceutically acceptable salt thereof, wherein G, R 1 -R 5 and are as defined in claim 2 .

9. The compound of claim 3 , having the Formula IX:

or a pharmaceutically acceptable salt thereof, wherein G, R 1 -R 5 and are as define in claim 3 .

10. The compound of claim 1 , wherein G is R 1 .

11. The compound of claim 10 , wherein R 1 is hydrogen.

12. The compound of claim 10 , wherein R 1 is C 1-4 alkyl, C 2-4 alkenyl or C 2-4 alkynyl.

13. The compound of claim 10 , wherein R 1 is C 3-6 cycloalkyl (C 1-4 )alkyl, or C 6-10 aryl(C 1-4 )alkyl, wherein the C 3-6 cycloalkyl and C 6-10 aryl portions are optionally substituted with 1,2, or 3 substituents, each independently selected from the group consisting of hydroxy, halo, halo(C 1-4 )alkyl, amino, C 1-4 alkylamino, di(C 1-4 )alkylamino, carboxy, and C 1-4 alkoxycarbonyl.

14. The compound of claim 1 , wherein G is PG.

15. The compound of claim 1 , wherein R 2 is hydrogen.

16. The compound of claim 1 , wherein R 2 is C 1-6 alkyl, C 2-6 alkenyl, or C 3-7 cycloalkyl (C 1-4 )alkyl any of which is optionally substituted with 1, 2, or 3 substituents, each independently selected from the group consisting of hydroxy, halo, halo(C 1-4 )alkyl, amino, C 1-4 alkylamino, di(C 1-4 )alkylamino, carboxy, and C 1-4 alkoxycarbonyl.

17. The compound of claim 16 , wherein R 2 is C 3-7 (cycloalkyl)(C 1-4 ) alkyl optionally substituted with 1, 2,or 3 substituents, each independently selected from the group consisting of hydroxy, halo, halo(C 1-4 )alkyl, amino, C 1-4 alkylamino, di(C 1-4 )alkylamino, carboxy, and C 1-4 alkoxycarbonyl.

18. The compound of claim 1 , wherein is a single bond.

19. The compound of claim 1 , wherein is a double bond.

20. The compound of claim 1 , wherein G is R 1 , R 3 is methyl and R 4 is tert-butyl having the Formula X:

or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 5 and are as defined in claim 1 .

21. The compound of claim 20 , having the Formula XI:

or a pharmaceutically acceptable salt thereof.

22. The compound of claim 20 , having the Formula XII:

or a pharmaceutically acceptable salt thereof.

23. The compound of claim 20 , wherein

R 1 is hydrogen, C 1-6 alkyl, or benzyl;

R 2 is C 2-6 alkenyl, cyclopropyl(C 1-4 )alkyl, cyclopentyl(C 1-4 )alkyl, or cyclohexyl(C 1-4 )alkyl, optionally substituted with 1, 2, or 3 substituents, each independently selected from the group consisting of hydroxy, halo, halo(C 1-4 )alkyl, amino, C 1-4 alkylamino, di(C 1-4 )alkylamino, carboxy, and C 1-4 alkoxycarbonyl; and

R 5 is hydrogen, C 1-6 alkyl, or phenyl.

24. The compound of claim 23 , wherein R 2 is unsubstituted C 2-6 alkenyl or unsubstituted cyclopropyl(C 1-4 )alkyl.

25. The compound of claim 1 , selected from the group consisting of

or a

pharmaceutically acceptable salt thereof.

26. A composition, comprising a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

27. A method of treating pain in a patient, comprising administering an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, to the patient in need of such treatment.

28. The method of claim 27 , wherein said pain is acute pain, chronic pain or surgical pain.

29. The method of claim 28 , wherein said pain is chronic pain.

30. The method of claim 29 , wherein said chronic pain is neuropathic pain, postoperative pain, or inflammatory pain.

31. A method of modulating one or more opioid receptors in a patient, comprising administering to the patient an effective amount of at least one compound as claimed in claim 1 , or a pharmaceutically acceptable salt thereof.

32. The method of claim 31 , wherein the μ- or κ-opioid receptor, or both, are modulated.

33. The compound as claimed in claim 1 , or a pharmaceutically acceptable salt, thereof, wherein the compound is 3 H, 11 C, or 14 C radiolabeled.

34. A method of preparing a pharmaceutical composition, comprising admixing a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable carrier.

35. A kit, comprising a container containing an effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and instructions for therapeutic use.

36. A process for preparing a compound of claim 1 having Formula I

comprising:

reacting a compound of Formula XIX

with (R 5 CH 2 ) 2 SO, wherein

R 5 is as defined in claim 1 ,

in the presence of a trialkylsilyl halide and an aprotic solvent to give a compound of Formula I.

37. The process of claim 36 , wherein said (R 5 CH 2 ) 2 SO is selected from the group consisting of dimethyl sulfoxide, di(n-propyl) sulfoxide, di(n-butyl) sulfoxide, and dibenzyl sulfoxide.

38. The process of claim 36 , wherein the trialkylsilyl halide is selected from the group consisting of trimethylsilyl chloride, trimethylsilyl bromide, trimethylsilyl iodide, or a combination thereof.

39. The process of claim 36 , wherein the process gives a compound of Formula XV:

wherein R 1 is hydrogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynl, C 3-6 cycloalkyl(C 1-4 )alkyl, or C 6-10 aryl(C 1-4 )alkyl, wherein the C 3-6 cycloalkyl, and C 6-10 aryl, portions thereof are optionally substituted with 1, 2, or 3 substituents, each independently

selected from the group consisting of hydroxy, halo, halo(C 1-4 )alkyl, amino, C 1-4 alkylamino, di(C 1-4 )alkylamino, carboxy, and C 1-4 alkoxycarbonyl; and

R 5 is as defined in claim 36 .

40. The compound of claim 5 , wherein R 5 is hydrogen, C 1-6 alkyl, or phenyl.

41. The compound of claim 6 , wherein R 5 is hydrogen, C 1-6 alkyl, or phenyl.