Analgesic compounds, methods, and formulations

1. A compound, or salt thereof, of formula I:

wherein A is

R 1 is hydrogen, C 1 -C 5 alkyl, C 1 -C 5 haloalkyl, C 1 -C 5 alkanol, —(C 1 -C 5 alkyl)phenyl, or phenyl, or a group of the formula —C(O)—R 12 , where R 12 is C 1 -C 5 alkyl, C 1 -C 5 alkoxy, C 1 -C 5 haloalkyl, C 1 -C 5 alkanol, —(C 1 -C 5 alkyl)phenyl, or phenyl;

R 2 is hydrogen, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, halogen, C 1 -C 5 haloalkyl, or C 1 -C 5 haloalkoxy;

R 3 is hydrogen, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, halogen, C 1 -C 5 haloalkyl, or C 1 -C 5 haloalkoxy;

R 4 is hydrogen, C 1 -C 5 alkyl, or —(C 1 -C 5 alkyl)phenyl;

R 5 is hydrogen, C 1 -C 5 alkyl, or —(C 1 -C 5 alkyl)phenyl;

R 6 is hydrogen, hydroxy, or is absent;

R 7 is hydrogen;

R 8 is hydrogen or methyl;

R 9 is hydrogen or methyl;

R 10 is hydrogen;

R 11 is hydrogen or C 1 -C 5 alkyl;

provided that one of A), B), and C) is present, wherein A), B) and C) are:

A) R 7 and R 10 combine to form —CH 2 — or —(CH 2 ) 2 —;

B) R 8 and R 9 combine to form a cyclopropyl group with the carbon to which they are attached; and

C) R 10 and R 11 combine to form —CH 2 — or —(CH 2 ) 3 .

2. The compound of claim 1 wherein A is selected from

3. The compound of claim 2 of the formula Ia:

or a salt thereof.

4. The compound of claim 2 wherein it is

2-dimethylaminomethyl-3-(3-methoxy-phenyl)-bicyclo[3.2.1]octan-3-ol;

2-dimethylaminomethyl-3-(3-fluoro-5-methoxy-phenyl)-bicyclo[3.2.1]octan-3-ol;

2-dimethylaminomethyl-3-(5-methoxy-2-trifluoromethoxy-phenyl)-bicyclo[3.2.1]octan-3-ol;

2-dimethylaminomethyl-3-(2-fluoro-5-methoxy-phenyl)-bicyclo[3.2.1]octan-3-ol;

2-dimethylaminomethyl-3-(4-fluoro-3-methoxy-phenyl)-bicyclo[3.2.1]octan-3-ol;

2-dimethylaminomethyl-3-(2-fluoro-3-methoxy-phenyl)-bicyclo[3.2.1]octan-3-ol;

2-dimethylaminomethyl-3-(3-methoxy-5-methyl-phenyl)-bicyclo[3.2.1]octan-3-ol;

3-(2-chloro-5-methoxy-phenyl)-2-dimethylaminomethyl-bicyclo[3.2.1]octan-3-ol;

3-(3-chloro-5-methoxyphenyl)-2-dimethylaminomethyl-bicyclo[3.2.1]octan-3-ol;

2-dimethylaminomethyl-3-(5-methoxy-2-methyl-phenyl)-bicyclo[3.2.1]octan-3-ol;

2-dimethylaminomethyl-3-(3-methoxy-4-methyl-phenyl)-bicyclo[3.2.1]octan-3-ol;

2-dimethylaminomethyl-3-(3-hydroxy-phenyl)-bicyclo[3.2.1]octan-3-ol;

2-dimethylaminomethyl-3-(2-fluoro-5-hydroxy-phenyl)-bicyclo[3.2.1]octan-3-ol;

2-dimethylaminomethyl-3-(3-fluoro-5-hydroxy-phenyl)-bicyclo[3.2.1]octan-3-ol;

2-dimethylaminomethyl-3-(3-hydroxy-5-trifluoromethyl-phenyl)-bicyclo[3.2.1]octan-3-ol;

2-dimethylaminomethyl-3-(5-hydroxy-2-trifluoromethoxy-phenyl)-bicyclo[3.2.1]octan-3-ol;

2-dimethylaminomethyl-3-(3-hydroxy-4-trifluoromethyl-phenyl)-bicyclo[3.2.1]octan-3-ol;

2-dimethylaminomethyl-3-(4-fluoro-3-hydroxy-phenyl)-bicyclo[3.2.1]octan-3-ol;

2-dimethylaminomethyl-3-(2-fluoro-3-hydroxy-phenyl)-bicyclo[3.2.1]octan-3-ol;

2-dimethylaminomethyl-3-(3-hydroxy-5-methyl-phenyl)-bicyclo[3.2.1]octan-3-ol;

3-(2-chloro-5-hydroxy-phenyl)-2-dimethylaminomethyl-bicyclo[3.2.1]octan-3-ol;

3-(3-chloro-5-hydroxy-phenyl)-2-dimethylaminomethyl-bicyclo[3.2.1]octan-3-ol;

2-dimethylaminomethyl-3-(5-hydroxy-2-methyl-phenyl)-bicyclo[3.2.1]octan-3-ol;

2-dimethylaminomethyl-3-(3-hydroxy-4-methyl-phenyl)-bicyclo[3.2.1]octan-3-ol;

3-(3,4-difluoro-5-hydroxy-phenyl)-2-dimethylaminomethyl-bicyclo[3.2.1]octan-3-ol;

2-dimethylaminomethyl-3-(2-fluoro-5-hydroxy-phenyl)-bicyclo[3.2.1]octan-3-ol;

2,2-dimethyl-propionic acid 3-(2-dimethylaminomethyl-3-hydroxy-bicyclo[3.2.1]oct-3-yl)-4-fluoro-phenyl ester;

benzoic acid 3-(2-dimethylaminomethyl-3-hydroxy-bicyclo[3.2.1]oct-3-yl)-4-fluoro-phenyl ester;

2,2-dimethyl-propionic acid 3-(2-dimethylaminomethyl-3-hydroxy-bicyclo[3.2.1]oct-3-yl)-phenyl ester;

benzoic acid 3-(2-dimethylaminomethyl-3-hydroxy-bicyclo[3.2.1]oct-3-yl)-phenyl ester;

2,2-dimethyl-propionic acid 3-(2-dimethylaminomethyl-3-hydroxy-bicyclo[3.2.1]oct-3-yl)-5-fluoro-phenyl ester; or

benzoic acid 3-(2-dimethylaminomethyl-3-hydroxy-bicyclo[3.2.1]oct-3-yl)-5-fluoro-phenyl ester;

or a salt thereof.

5. The compound of claim 2 of the formula Ib:

or a salt thereof.

6. The compound of claim 2 wherein it is

3-(4-dimethylaminomethyl-bicyclo[3.2.1]oct-2-en-3-yl)-phenol;

[3-(3-methoxy-phenyl)-bicyclo[3.2.1]oct-3-en-2-ylmethyl]-dimethyl-amine;

[3-(5-methoxy-2-trifluoromethoxy-phenyl)-bicyclo[3.2.1]oct-3-en-2-ylmethyl]-dimethyl-amine;

3-(4-dimethylaminomethyl-bicyclo[3.2.1]oct-2-en-3-yl)-4-trifluoromethoxy-phenol;

[3-(3-fluoro-5-methoxy-phenyl)-bicyclo[3.2.1]oct-3-en-2-ylmethyl]-dimethyl-amine;

3-(4-dimethylaminomethyl-bicyclo[3.2.1]oct-2-en-3-yl)-5-fluoro-phenol;

[3-(2-fluoro-5-methoxy-phenyl)-bicyclo[3.2.1]oct-3-en-2-ylmethyl]-dimethyl-amine;

3-(4-dimethylaminomethyl-bicyclo[3.2.1]oct-2-en-3-yl)-4-fluoro-phenol;

[3-(3-methoxy-5-methyl-phenyl)-bicyclo[3.2.1]oct-3-en-2-ylmethyl]-dimethyl-amine;

3-(4-dimethylaminomethyl-bicyclo[3.2.1]oct-2-en-3-yl)-5-methyl-phenol;

3-chloro-5-(4-dimethylaminomethyl-bicyclo[3.2.1]oct-2-en-3-yl)-phenol;

[3-(5-methoxy-2-methyl-phenyl)-bicyclo[3.2.1]oct-3-en-2-ylmethyl]-dimethyl-amine;

3-(4-dimethylaminomethyl-bicyclo[3.2.1]oct-2-en-3-yl)-4-methyl-phenol;

4-chloro-3-(4-dimethylaminomethyl-bicyclo[3.2.1]oct-2-en-3-yl)-phenol;

2,2-dimethyl-propionic acid 3-(4-dimethylaminomethyl-bicyclo[3.2.1]oct-2-en-3-yl)-phenyl ester;

benzoic acid 3-(4-dimethylaminomethyl-bicyclo[3.2.1]oct-2-en-3-yl)-phenyl ester;

2,2-dimethyl-propionic acid 3-(4-dimethylaminomethyl-bicyclo[3.2.1]oct-2-en-3-yl)-5-fluorophenyl ester;

isobutyric acid 3-(4-dimethylaminomethyl-bicyclo[3.2.1]oct-2-en-3-yl)-5-fluoro-phenyl ester;

2,2-dimethyl-propionic acid 3-(4-dimethylaminomethyl-bicyclo[3.2.1]oct-2-en-3-yl)-4-fluoro-phenyl ester; or

isobutyric acid 3-(4-dimethylaminomethyl-bicyclo[3.2.1]oct-2-en-3-yl)-4-fluoro-phenyl ester;

or a salt thereof.

7. The compound of claim 2 wherein it is of the formula Ic:

or a salt thereof.

8. The compound of claim 2 wherein it is:

3-(2-dimethylaminomethyl-bicyclo[3.2.1]oct-3-yl)-phenol;

[3-(3-methoxy-phenyl)-bicyclo[3.2.1]oct-2-ylmethyl]-dimethyl-amine;

3-(2-dimethylaminomethyl-bicyclo[3.2.1]oct-3-yl)-5-fluoro-phenol;

[3-(3-fluoro-5-methoxy-phenyl)-bicyclo[3.2.1]oct-2-ylmethyl]-dimethyl-amine;

3-(2-dimethylaminomethyl-bicyclo[3.2.1]oct-3-yl)-4-fluoro-phenol;

[3-(2-fluoro-5-methoxy-phenyl)-bicyclo[3.2.1]oct-2-ylmethyl]-dimethyl-amine;

3-(2-dimethylaminomethyl-bicyclo[3.2.1]oct-3-yl)-5-methyl-phenol;

[3-(3-methoxy-5-methyl-phenyl)-bicyclo[3.2.1]oct-2-ylmethyl]-dimethyl-amine;

2,2-dimethyl-propionic acid 3-(2-dimethylaminomethyl-bicyclo[3.2.1]oct-3-yl)-phenyl ester;

benzoic acid 3-(2-dimethylaminomethyl-bicyclo[3.2.1]oct-3-yl)-phenyl ester;

2,2-dimethyl-propionic acid 3-(2-dimethylaminomethyl-bicyclo[3.2.1]oct-3-yl)-5-fluoro-phenyl ester;

isobutyric acid 3-(2-dimethylaminomethyl-bicyclo[3.2.1]oct-3-yl)-5-fluoro-phenyl ester;

2,2-dimethyl-propionic acid 3-(2-dimethylaminomethyl-bicyclo[3.2.1]oct-3-yl)-4-fluoro-phenyl ester;

or isobutyric acid 3-(2-dimethylaminomethyl-bicyclo[3.2.1]oct-3-yl)-4-fluoro-phenyl ester;

or a salt thereof.

9. The compound of claim 2 wherein it is of the formula Id:

or a salt thereof.

10. The compound of claim 2 wherein it is

3-dimethylaminomethyl-2-(3-hydroxy-phenyl)-bicyclo[4.1.0]heptan-2-ol;

3-dimethylaminomethyl-2-(3-methoxy-phenyl)-bicyclo[4.1.0]heptan-2-ol;

3-dimethylaminomethyl-2-(3-fluoro-5-methoxy-phenyl)-bicyclo[4.1.0]heptan-2-ol;

3-dimethylaminomethyl-2-(5-methoxy-2-methyl-phenyl)-bicyclo[4.1.0]heptan-2-ol;

3-dimethylaminomethyl-2-(3-methoxy-phenyl)-5,5-dimethyl-bicyclo[4.1.0]heptan-2-ol;

3-dimethylaminomethyl-2-(3-hydroxy-phenyl)-5,5-dimethyl-bicyclo[4.1.0]heptan-2-ol;

3-dimethylaminomethyl-2-(3-fluoro-5-hydroxy-phenyl)-bicyclo[4.1.0]heptan-2-ol;

3-dimethylaminomethyl-2-(2-fluoro-5-hydroxy-phenyl)-bicyclo[4.1.0]heptan-2-ol;

3-dimethylaminomethyl-2-(3-hydroxy-5-methyl-phenyl)-bicyclo[4.1.0]heptan-2-ol;

2,2-dimethyl-propionic acid 3-(3-dimethylaminomethyl-2-hydroxy-bicyclo[4.1.0]hept-2-yl)-5-fluoro-phenyl ester; or

2,2-dimethyl-propionic acid 3-(3-dimethylaminomethyl-2-hydroxy-bicyclo[4.1.0]hept-2-yl)-4-fluoro-phenyl ester;

or a salt thereof.

11. The compound of claim 2 wherein it is of the formula Ie:

or a salt thereof.

12. The compound of claim 11 wherein it is

(1R,2R,3S,4S,5S)-3-(3-hydroxyphenyl)-2,6,6-trimethyl-4-((methyl(phenethyl)amino)methyl)bicyclo[3.1.1]heptan-3-ol;

(1R,2R,3S,4S,5S)-3-(3-methoxyphenyl)-2,6,6-trimethyl-4-((methyl(phenethyl)amino)methyl)bicyclo[3.1.1]heptan-3-ol;

(1S,2S,3R,4R,5R)-3-(3-hydroxyphenyl)-2,6,6-trimethyl-4-((methyl(phenethyl)amino)methyl)bicyclo[3.1.1]heptan-3-ol;

(1S,2S,3R,4R,5R)-3-(3-methoxyphenyl)-2,6,6-trimethyl-4-((methyl(phenethyl)amino)methyl)bicyclo[3.1.1]heptan-3-ol;

or a salt thereof.

13. The compound of claim 2 wherein it is of the formula If:

or a salt thereof.

14. The compound of claim 13 wherein it is 5-((dimethylamino)methyl)-4-(3-hydroxyphenyl)octahydro-1H-inden-4-ol, or a salt thereof.

15. The compound of claim 2 wherein it is (+)-(1S,2R,3R,5R)-2-((dimethylamino)methyl)-3-(3-hydroxyphenyl)bicyclo[3.2.1]octan-3-ol;

(−)-(1R,2S,3S,5S)-2-((dimethylamino)methyl)-3-(3-hydroxyphenyl)bicyclo[3.2.1]octan-3-ol;

(S)-3-((1S,2R,3R,5R)-2-((dimethylamino)methyl)-3-hydroxybicyclo[3.2.1]octan-3-yl)phenyl 2-phenylpropanoate hydrochloride;

(S)-3-(1R,2S,3S,5S)-2-((dimethylamino)methyl)-3-hydroxybicyclo[3.2.1]octan-3-yl)phenyl 2-phenylpropanoate hydrochloride;

3-(4-dimethylaminomethyl-bicyclo[3.2.1]oct-2-en-3-yl)-phenol;

3-((1S,5R)-2-((dimethylamino)methyl)bicyclo[3.2.1]oct-2-en-3-yl)phenol; and salty or a salt thereof.

16. A compound of claim 2 wherein it is of the formula Ig:

or a salt thereof.

17. The compound of claim 16 where it is 5-dimethylaminomethyl-6-(2-fluoro-5-hydroxy-phenyl)-spiro[2.5]octan-6-ol, or a salt thereof.

18. The compound of claim 4 wherein it is 2-dimethylaminomethyl-3-(3-methoxy-5-methyl-phenyl)-bicyclo[3.2.1]octan-3-ol, or a salt thereof.

19. The compound of claim 4 wherein it is 2-dimethylaminomethyl-3-(3-hydroxy-5-methyl-phenyl)-bicyclo[3.2.1]octan-3-ol, or a salt thereof.

20. The compound of claim 10 wherein it is 3-dimethylaminomethyl-2-(3-fluoro-5-hydroxy-phenyl)-bicyclo[4.1.0]heptan-2-ol, or a salt thereof.

21. The compound of claim 10 wherein it is 3-dimethylaminomethyl-2-(2-fluoro-5-hydroxy-phenyl)-bicyclo[4.1.0]heptan-2-ol, or a salt thereof.

22. The compound of claim 10 wherein it is 2,2-dimethyl-propionic acid 3-(3-dimethylaminomethyl-2-hydroxy-bicyclo[4.1.0]hept-2-yl)-5-fluoro-phenyl ester, or a salt thereof.

23. The compound of claim 10 wherein it is 2,2-dimethyl-propionic acid 3-(3-dimethylaminomethyl-2-hydroxy-bicyclo[4.1.0]hept-2-yl)-4-fluoro-phenyl ester, or a salt thereof.

24. A pharmaceutical formulation comprising a compound claim 2 and one or more pharmaceutically acceptable carriers.

25. The pharmaceutical formulation of claim 24 wherein it further comprises at least one additional active ingredient.

26. The pharmaceutical formulation of claim 24 wherein it is a human pharmaceutical formulation.

27. The pharmaceutical formulation of claim 24 wherein it is a veterinary pharmaceutical formulation.

28. A method of controlling pain in a mammal in need thereof comprising administering an effective amount of a compound of claim 1 to said mammal.

29. The method of claim 28 wherein at least one other active ingredient is administered to said mammal.

30. The method of claim 28 wherein said mammal is a human.

31. The method of claim 28 wherein said mammal is a companion animal.