Opioid compounds and uses thereof

1. A compound of Formula IV:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

R 1 is hydrogen; C 1-6 alkyl optionally substituted with 1, 2, or 3 substituents, each substituent 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, C 1-4 alkoxy, and C 1-4 alkoxycarbonyl; or -PEG-R 7 ;

R 4 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, and (C 3-6 cycloalkyl)(C 1-4 )alkyl, any of which is optionally substituted with 1, 2, or 3 substituents, each substituent 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, C 1-4 alkoxy, and C 1-4 alkoxycarbonyl;

R 5 is selected from the group consisting of unsubstituted C 1-6 alkyl, —CH 2 —O—(CH 2 CH 2 O) m —R 7 , —O—(CH 2 CH 2 O) n —R 7 , and —NH—(CH 2 CH 2 O) p —R 7 ;

R 7 is selected from the group consisting of hydrogen and C 1-6 alkyl;

R 31 is hydrogen or hydroxy;

m is an integer between 1 and 9;

n and p are each independently an integer between 1 and 20; and

PEG is one ethylene oxide unit or an oligomer of 2 to about 10 ethylene oxide subunits, provided that the compound is not

2. The compound of claim 1 , which is

or a pharmaceutically acceptable salt or solvate thereof.

3. The compound of claim 1 , which is

or a pharmaceutically acceptable salt or solvate thereof.

4. A compound of Formula II:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

R 1 is hydrogen; C 1-6 alkyl optionally substituted with 1, 2, or 3 substituents, each substituent 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, C 1-4 alkoxy, and C 1-4 alkoxycarbonyl; or -PEG-R 7 ;

R 4 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, and (C 3-6 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(Ci-4)alkylamino, carboxy, C 1-4 alkoxy, and C 1-4 alkoxycarbonyl;

R 2 is —C(═O)R 5 and R 3 is —OC(═O)R 6 , wherein

R 5 is selected from the group consisting of a straight-chain unsubstituted C 7-9 alkyl, —CH 2 —O—(CH 2 CH 2 O) m —R 7 , —O—(CH 2 CH 2 O) n —R 7 , and —NH—(CH 2 CH 2 O) p —R 7 ;

R 6 is selected from the group consisting of a straight-chain unsubstituted C 7-9 alkyl, a straight-chain unsubstituted C 7-9 alkenyl, a straight-chain unsubstituted C 7-9 alkynyl, —CH 2 —O—(CH 2 CH 2 O) m —R 7 , —O—(CH 2 CH 2 O) n —R 7 , and —NH—(CH 2 CH 2 O) p —R 7 ;

R 7 is selected form the group consisting of hydrogen and C 1-6 alkyl;

m is 2 or 3;

n and p are each independently 2, 3, or 4; and

PEG is one ethylene oxide unit or an oligomer of 2 to about 10 ethylene oxide subunits.

5. The compound of claim 4 , which is

or a pharmaceutically acceptable salt or solvate thereof.

6. A compound of Formula II:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

R 1 is hydrogen; C 1-6 alkyl optionally substituted with 1, 2, or 3 substituents, each substituent 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, C 1-4 alkoxy, and C 1-4 alkoxycarbonyl; or -PEG-R 7 ;

R 4 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, and (C 3-6 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(Ci-4)alkylamino, carboxy, C 1-4 alkoxy, and C 1-4 alkoxycarbonyl;

R 2 is —C(═O)R 5 and R 3 is —OC(═O)R 6 , wherein

R 5 is selected from the group consisting of a straight-chain unsubstituted C 10-12 alkyl, —CH 2 —O—(CH 2 CH 2 O) m —R 7 , —O—(CH 2 CH 2 O) n —R 7 , and —NH—(CH 2 CH 2 O) p —R 7 ;

R 6 is selected from the group consisting of a straight-chain unsubstituted C 10-12 alkyl, a straight-chain unsubstituted C 10-12 alkenyl, a straight-chain unsubstituted C 10-12 alkynyl, —CH 2 —O—(CH 2 CH 2 O) m —R 7 , —O—(CH 2 CH 2 O) n —R 7 , and —NH—(CH 2 CH 2 O) p —R 7 ;

R 7 is selected form the group consisting of hydrogen and C 1-6 alkyl;

m is an integer between 4 and 9;

n and p are each independently an integer between 4 and 20; and

PEG is one ethylene oxide unit or an oligomer of 2 to about 10 ethylene oxide subunits.

7. The compound of claim 6 , which is

or a pharmaceutically acceptable salt or solvate thereof.

8. A compound, which is

or a pharmaceutically acceptable salt or solvate thereof.

9. A composition, comprising one or more compounds of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, and at least one parent opioid.

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

11. A method of slowing the onset of activity of an opioid in a mammal in need of opioid therapy, comprising orally administering to the mammal a therapeutically effective amount of the compound or a mixture of the compounds according to claim 1 , or a pharmaceutically acceptable salt or solvate thereof.

12. A method of slowing the onset of activity of an opioid in a mammal in need of opioid therapy, comprising orally administering to the mammal a therapeutically effective amount of the compound or a mixture of the compounds according to claim 6 , or a pharmaceutically acceptable salt or solvate thereof.

13. A method of treating or ameliorating pain in a patient in need thereof, comprising administering an effective amount of a compound of

or a pharmaceutically acceptable salt or solvate thereof, to provide the patient a slowed onset of an oxycodone treatment.

14. The method of claim 12 , comprising orally administering a compound or a mixture of compounds having Formula V:

or a pharmaceutically acceptable salt or solvate thereof, wherein

R 1 is hydrogen H or unsubstituted C 1-6 alkyl;

R 4 is unsubstituted C 1-6 alkyl; and

R 5 is decyl, undecyl, or dodecyl.

15. A pharmaceutical composition comprising the compound of claim 1 and one or more pharmaceutically acceptable carriers.

16. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is hydrogen or unsubstituted C 1-6 alkyl and R 4 is unsubstituted C 1-6 alkyl.

17. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 31 is hydroxy.

18. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is unsubstituted C 1-6 alkyl.

19. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein

R 5 is selected from the group consisting of —CH 2 —O—(CH 2 CH 2 O) m —R 7 , —O—(CH 2 CH 2 O) n —R 7 , and —NH—(CH 2 CH 2 O) p —R 7 ;

R 7 is hydrogen or C 1-4 alkyl;

m is 1, 2, 3, 4, or 5;

n and p are each independently selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.

20. The compound of claim 19 , or a pharmaceutically acceptable salt thereof, wherein R 7 is hydrogen or methyl.

21. The compound of claim 19 , or a pharmaceutically acceptable salt thereof, wherein R 5 is —CH 2 —O—(CH 2 CH 2 O) m —R 7 .

22. The compound of claim 19 , or a pharmaceutically acceptable salt thereof, wherein m is 1, 2, or 3.

23. The compound of claim 4 , wherein R 5 and R 6 are the same, having the Formula V:

or a pharmaceutically acceptable salt or solvate thereof.

24. The compound of claim 23 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 is —CH 2 —O—(CH 2 CH 2 O) m —R 7 , wherein R 7 is hydrogen or methyl.

25. The compound of claim 4 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is hydrogen or unsubstituted C 1-6 alkyl and R 4 is unsubstituted C 1-6 alkyl.

26. The compound of claim 4 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 and R 4 are methyl.