Opioid antagonists

1. A compound of formula III:

wherein:

R 1 is —OH, —OR a , —CH 2 OH, —C(═O)OR 6 , —C(═O)NR 6 R 7 , or —NR 6 R 7 ;

R 2 and R 3 are each independently alkyl or alkenyl;

R 4 is H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, aralkyl, alkylaralkyl, or heteroarylalkyl;

X is CH 2 ;

R 6 is H, alkyl, cycloalkyl, alkylcycloalkyl, or aralkyl;

R 7 is H, alkyl, aralkyl, or aryl;

R a is a hydroxyl protecting group;

m is 1; and

n is 1

or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 , wherein R 1 is —OH or —C(═O)NR 6 R 7 .

3. A compound according to claim 2 , having the structure of formula IVa:

4. A compound according to claim 3 , having the structure of formula IVb:

5. A compound according to claim 1 , wherein R 2 and R 3 are each independently C 1 -C 3 alkyl.

6. A compound according to claim 5 , wherein R 2 and R 3 are each methyl.

7. A compound according to claim 1 , wherein R 4 is H, alkyl, cycloalkyl, aryl, or aralkyl.

8. A compound according to claim 7 , wherein R 4 is C 1 -C 3 alkyl.

9. A compound according to claim 8 , wherein R 4 is isopropyl.

10. A compound according to claim 1 , wherein the compound is:

3-(2,3-dimethyl-octahydro-1 H-quinolizin-2-yl)phenol;

or a pharmaceutically acceptable salt thereof.

11. A compound according to claim 1 , wherein the compound is:

3-((2R,3R,9□R)-2,3-dimethyl-octahydro-1H-quinolizin-2-yl)phenol; or

3-((2R,3R,9□S)-2,3-dimethyl-octahydro-1H-quinolizin-2-yl)phenol;

or a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition, comprising:

a pharmaceutically acceptable carrier; and

an effective amount of a compound according to claim 2 .

13. A pharmaceutical composition comprising:

a pharmaceutically acceptable carrier;

an effective amount of at least one opioid; and

an effective amount of a compound of Formula IIIa:

wherein:

R 1 is —OH, —CH 2 OH, —C(═O)OR 6 , —C(═O)NR 6 R 7 , or —NR 6 R 7 ;

R 2 and R 3 are each independently alkyl or alkenyl;

R 4 is H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, aralkyl, alkylaralkyl, or heteroarylalkyl;

X is CH 2 ;

R 6 is H, alkyl, cycloalkyl, alkylcycloalkyl, or aralkyl;

R 7 is H, alkyl, aralkyl, or aryl;

m is 1; and

n is 1

or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition according to claim 13 ,

wherein the opioid is alfentanil, buprenorphine, butorphanol, codeine, dezocine, dihydrocodeine, fentanyl, hydrocodone, hydromorphone, levorphanol, meperidine (pethidine), methadone, morphine, nalbuphine, oxycodone, oxymorphone, pentazocine, propiram, propoxyphene, sufentanil, tramadol or mixtures thereof.

15. A method of binding opioid receptors in a patient in need thereof, comprising the step of:

administering to the patient a composition comprising an effective amount of a compound of formula IIIa:

wherein:

R 1 is —OH, —CH 2 OH, —C(═O)OR 6 , —C(═O)NR 6 R 7 , or —NR 6 R 7 ;

R 2 and R 3 are each independently alkyl or alkenyl;

R 4 is H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, aralkyl, alkylaralkyl, or heteroarylalkyl;

X is CH 2 ;

R 6 is H, alkyl, cycloalkyl, alkylcycloalkyl, or aralkyl;

R 7 is H, alkyl, aralkyl, or aryl;

m is 1; and

n is 1

or a pharmaceutically acceptable salt thereof.

16. A method according to claim 15 ,

wherein the compound binds μ opioid receptors.

17. A method according to claim 16 ,

wherein the μ opioid receptors are located in the central nervous system.

18. A method according to claim 16 ,

wherein the μ opioid receptors are located peripherally to the central nervous system.

19. A method according to claim 15 ,

wherein the compound binds κ opioid receptors.

20. A method according to claim 19 ,

wherein the κ opioid receptors are located in the central nervous system.

21. A method according to claim 19 ,

wherein the κ opioid receptors are located peripherally to the central nervous system.

22. A method according to claim 15 ,

wherein the compound binds □ opioid receptors.

23. A method according to claim 22 ,

wherein the □ opioid receptors are located in the central nervous system.

24. A method according to claim 22 ,

wherein the □ opioid receptors are located peripherally to the central nervous system.

25. A method according to claim 15 ,

wherein the compound exhibits antagonist activity toward the opioid receptors.

26. A method of treating ileus, comprising the step of:

administering to a patient in need thereof, a composition comprising an effective amount of a compound of formula IIIa:

wherein:

R 1 is —OH, —CH 2 OH, —C(═O)OR 6 , —C(═O)NR 6 R 7 , or —NR 6 R 7 ;

R 2 and R 3 are each independently alkyl or alkenyl;

R 4 is H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, aralkyl, alkylaralkyl, or heteroarylalkyl;

X is CH 2 ;

R 6 is H, alkyl, cycloalkyl, alkylcycloalkyl, or aralkyl;

R 7 is H, alkyl, aralkyl, or aryl;

m is 1; and

n is 1

or a pharmaceutically acceptable salt thereof.

27. A method according to claim 26 ,

wherein the ileus is post-operative ileus.

28. A method of treating pain, comprising the step of:

administering to a patient in need thereof, a composition comprising:

an effective amount of an opioid; and

an effective amount of a compound of formula IIIa:

wherein

R 1 is —OH, —CH 2 OH, —C(═O)OR 6 , —C(═O)NR 6 R 7 , or —NR 6 R 7 ;

R 2 and R 3 are each independently alkyl or alkenyl;

R 4 is H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, aralkyl, alkylaralkyl, or heteroarylalkyl;

X is CH 2 ;

R 6 is H, alkyl, cycloalkyl, alkylcycloalkyl, or aralkyl;

R 7 is H, alkyl, aralkyl, or aryl;

m is 1; and

n is 1

or a pharmaceutically acceptable salt thereof.

29. A method according to claim 28 ,

wherein the opioid is alfentanil, buprenorphine, butorphanol, codeine, dezocine, dihydrocodeine, fentanyl, hydrocodone, hydromorphone, levorphanol, meperidine (pethidine), methadone, morphine, nalbuphine, oxycodone, oxymorphone, pentazocine, propiram, propoxyphene, sufentanil, tramadol or mixtures thereof.

30. A compound according to claim 1 , wherein R 4 is aryl.

31. A compound according to claim 30 , wherein R 4 is C 6 aryl.

32. A compound according to claim 31 , wherein R 4 is phenyl.