Buprenorphine derivatives and uses thereof
View Patent ↗Ester derivatives of the phenolic hydroxyl group of buprenorphine can be used in the treatment of opiate dependency and/or moderate to severe pain. The esters have an enhanced bioavailability, an enhanced duration of action, and a reduced abuse potential.
1. Compounds of Structure I, or salts thereof:
wherein R 1 is
(1) C 1 -C 10 straight-chain or branched alkylene, optionally substituted with an aromatic ring,
(2) —(CH 2 ) p CH═CH(CH 2 ) p —, in which each p is independently an integer from 0 to 4,
or
(3) —(CH 2 )—X(CH 2 ) n —, in which each n is an integer from 0 to 2, X is O, S, NH, N(COOCH 2 Ph),
having 1,2-, 1,3-, or 1,4-substitution, in which Y is O, S or NH,
having 1,2-, 1,3-, or 1,4-substitution or
in which m is an integer from 1 to 4;
and wherein R 2 is H or C 1 -C 6 straight-chain or branched alkyl.
2. Compounds of claim 1 , wherein R 1 is selected from the group consisting of
—CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 —, —CH 2 CH(CH 3 )CH 2 —, —CH 2 C(CH 3 ) 2 CH 2 —, —CH 2 OCH 2 —, —CH 2 SCH 2 —, —CH 2 NHCH 2 — and —CH 2 N(COOCH 2 Ph)CH 2 —.
3. Compounds of claim 2 , wherein R 2 is H.
4. Compounds of Structure IA, or salts thereof:
wherein R 1 is
(1) C 1 -C 10 straight-chain alkylene,
(2) C 1 -C 8 straight-chain alkylene substituted with from 1 to 4 methyl groups or a phenyl group,
or
(3) —(CH 2 ) p CH═CH(CH 2 ) p —, in which each p is independently an integer from 0 to 3.
5. Compounds of claim 4 , wherein R 1 is C 2 -C 5 straight-chain alkylene.
6. Compounds of claim 5 , wherein R 1 is selected from the group consisting of —CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 — and —CH 2 CH 2 CH 2 CH 2 CH 2 —.
7. The compound of claim 6 , wherein R 1 is —CH 2 CH 2 CH 2 —.
8. The compound of claim 6 , wherein R 1 is —CH 2 CH 2 CH 2 CH 2 —.
9. Compounds of claim 4 , wherein R 1 is —CH 2 CH(CH 3 )CH 2 — or —CH 2 C(CH 3 ) 2 CH 2 —.
10. Compounds of Structure II, or salts thereof:
wherein each n is an integer from 0 to 2, and X is O, S, NH, N(COOCH 2 Ph),
having 1,2-, 1,3-, or 1,4-substitution, in which Y is O, S or NH,
having 1,2-, 1,3-, or 1,4-substitution or
in which m is an integer from 1 to 4.
11. Compounds of claim 10 , wherein each n is 1.
12. Compounds of claim 11 , wherein X is S, NH or N(COOCH 2 Ph).
13. The compound of claim 11 , wherein X is O.
14. The compound of Structure IA1:
15. The compound of Structure IA2:
16. A pharmaceutical composition comprising
(A) a compound of Structure I, or a salt thereof:
wherein R 1 is
(1) C 1 -C 10 straight-chain or branched alkylene, optionally substituted with an aromatic ring,
(2) —(CH 2 ) p CH═CH(CH 2 ) p —, in which each p is independently an integer from 0 to 4,
or
(3) —(CH 2 )—X(CH 2 ) n —, in which each n is an integer from 0 to 2, X is O, S, NH, N(COOCH 2 Ph),
having 1,2-, 1,3-, or 1,4-substitution, in which Y is O, S or NH,
having 1,2-, 1,3-, or 1,4-substitution or
in which m is an integer from 1 to 4;
and wherein R 2 is H or C 1 -C 6 straight-chain or branched alkyl, and
(B) a pharmaceutically acceptable carrier.
17. A pharmaceutical composition according to claim 16 in which the compound has Structure IA or a salt thereof:
wherein R 1 is
(1) C 1 -C 10 straight-chain alkylene,
(2) C 1 -C 8 straight-chain alkylene substituted with from 1 to 4 methyl groups or a phenyl group,
or
(3) —(CH 2 ) p CH═CH(CH 2 ) p —, in which each p is independently an integer from 0 to 3.
18. A pharmaceutical composition according to claim 16 in which the compound has Structure II or a salt thereof:
wherein each n is an integer from 0 to 2, and X is O, S, NH, N(COOCH 2 Ph),
having 1,2-, 1,3-, or 1,4-substitution, in which Y is O, S or NH,
having 1,2-, 1,3-, or 1,4-substitution, or
in which m is an integer from 1 to 4.
19. A composition according to claim 17 in which the compound has Structure IA1:
20. A composition according to claim 17 in which the compound has the structure IA2:
21. A method of treating opiate abuse and/or dependence in a subject, the method comprising administering to the subject a therapeutically effective amount of one or more compounds of the Structure I, or salts thereof:
wherein R 1 is
(1) C 1 -C 10 straight-chain or branched alkylene, optionally substituted with an aromatic ring,
(2) —(CH 2 ) p CH═CH(CH 2 ) p —, in which each p is independently an integer from 0 to 4,
or
(3) —(CH 2 )—X(CH 2 ) n —, in which each n is an integer from 0 to 2, X is O, S, NH, N(COOCH 2 Ph),
having 1,2-, 1,3-, or 1,4-substitution, in which Y is O, S or NH,
having 1,2-, 1,3-, or 1,4-substitution or
in which m is an integer from 1 to 4;
and wherein R 2 is H or C 1 -C 6 straight-chain or branched alkyl.
22. A method according to claim 21 , in which is the compounds, R 1 is selected from the group consisting of —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 —, —CH 2 CH(CH 3 )CH 2 —, —CH 2 C(CH 3 ) 2 CH 2 —, —CH 2 OCH 2 —, —CH 2 SCH 2 —, —CH 2 NHCH 2 — and —CH 2 N(COOCH 2 Ph)CH 2 —.
23. A method according to claim 22 in which, in the compounds, R 2 is H.
24. A method according to claim 21 in which the compounds have the structure IA, or salts thereof:
wherein R 1 is
(1) C 1 -C 10 straight-chain alkylene,
(2) C 1 -C 8 straight-chain alkylene substituted with from 1 to 4 methyl groups or a phenyl group,
or
(3) —(CH 2 ) p CH═CH(CH 2 ) p —, in which each p is independently an integer from 0 to 3.
25. A method according to claim 24 in which, in the compounds, R 1 is C 2 -C 5 straight-chain alkylene.
26. A method according to claim 25 in which, in the compounds, R 1 is selected from the group consisting of —CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 — and —CH 2 CH 2 CH 2 CH 2 CH 2 —.
27. A method according to claim 26 in which, in the compounds, R 1 is —CH 2 CH 2 CH 2 —, or —CH 2 CH 2 CH 2 CH 2 —.
28. A method according to claim 21 in which the compounds have the Structure II or salts thereof:
wherein each n is an integer from 0 to 2, and X is O, S, NH, N(COOCH 2 Ph),
having 1,2-, 1,3-, or 1,4-substitution, in which Y is O, S or NH,
having 1,2-, 1,3-, or 1,4-substitution, or
in which m is an integer from 1 to 4.
29. A method according to claim 28 in which, in the compounds, each n is 1.
30. A method according to claim 29 in which, in the compounds, X is S, NH or N(COOCH 2 Ph).
31. A method according to claim 29 in which, in the compound, X is O.
32. A method according to claim 24 in which the compound has the Structure IA1:
33. A method according to claim 24 in which the compound has the structure IA2:
34. A method according to claim 21 in which the one or more compounds is administered orally or sublingually.
35. A method of relieving or treating moderate to severe pain in a subject, the method comprising administering to the subject a therapeutically effective amount of one or more compounds of the Structure I, or salts thereof:
wherein R 1 is
(1) C 1 -C 10 straight-chain or branched alkylene, optionally substituted with an aromatic ring,
(2) —(CH 2 ) p CH═CH(CH 2 ) p —, in which each p is independently an integer from 0 to 4,
or
(3) —(CH 2 )—X(CH 2 ) n —, in which each n is an integer from 0 to 2, X is O, S, NH, N(COOCH 2 Ph),
having 1,2-, 1,3-, or 1,4-substitution, in which Y is O, S or NH,
having 1,2-, 1,3-, or 1,4-substitution or
in which m is an integer from 1 to 4;
and wherein R 2 is H or C 1 -C 6 straight-chain or branched alkyl.
36. A method according to claim 35 in which the compounds have the structure IA, or salts thereof:
wherein R 1 is
(1) C 1 -C 10 straight-chain alkylene,
(2) C 1 -C 8 straight-chain alkylene substituted with from 1 to 4 methyl groups or a phenyl group,
or
(3) —(CH 2 ) p CH═CH(CH 2 ) p —, in which each p is independently an integer from 0 to 3.
37. A method according to claim 35 in which the compounds have the Structure II or salts thereof:
wherein each n is an integer from 0 to 2, and X is O, S, NH, N(COOCH 2 Ph),
having 1,2-, 1,3-, or 1,4-substitution, in which Y is O, S or NH,
having 1,2-, 1,3-, or 1,4-substitution, or
in which m is an integer from 1 to 4.
38. A method according to claim 35 in which the compound has the Structure IA1:
39. A method according to claim 35 in which the compound has the structure IA2: