Novel opioid compounds and uses thereof

文档序号：1026592 发布日期：2020-10-27 浏览：16次中文

阅读说明：本技术 新型阿片样化合物及其用途 (Novel opioid compounds and uses thereof ) 是由张平武雷蒙德·格洛瓦基迈克尔·大卫·罗格斯于 2019-02-22 设计创作，主要内容包括：本发明涉及新型的式I的阿片样物质衍生物：<Image he="371" wi="510" file="DDA0002641887010000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>或其药学上可接受的盐或溶剂合物,其中R1、R3、R4和Z如本文在本公开中所定义。本发明还涉及此类化合物用于治疗或预防例如疼痛的用途。(The present invention relates to novel opioid derivatives of formula I: or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 、R 3 、R 4 And Z is as defined herein in the present disclosure. The invention also relates to the use of such compounds for the treatment or prevention of, for example, pain.)

1. A compound of formula I:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

R¹is H; alkyl optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of: hydroxy, halo, haloalkyl, amino, alkylamino, dialkylamino, carboxy, alkoxy, and alkoxycarbonyl; -PEG-R⁷(ii) a Or a hydroxyl protecting group PG selected from the group consisting of: an alkyl group, an arylalkyl group, a heterocyclyl group, a (heterocyclyl) alkyl group, an acyl group, a silyl group, and a carbonate group, any of which groups is optionally substituted;

Z is C-OR²Or C (═ O);

R²is-C (═ O) R⁵or-PEG-R⁷Wherein

R⁵Selected from the group consisting of: unsubstituted C_1-12Alkyl, unsubstituted C_2-12Alkenyl, unsubstituted C_2-12Alkynyl, -CH₂-O-(CH₂CH₂O)_m-R⁷、-O-(CH₂CH₂O)_n-R⁷、-NH-(CH₂CH₂O)_p-R⁷Phenyl, benzyl, phenethyl, pyridyl, cycloalkyl, (cycloalkyl) alkyl, cycloalkenyl, (cycloalkenyl) alkyl, 6-membered heterocycle and (5-or 6-membered heterocycle) alkyl, wherein the phenyl, pyridyl, or heteroaryl is substituted with one or more substituents selected from the group consisting of alkyl, heteroaryl,The cycloalkyl, cycloalkenyl and heterocyclic moieties are optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of: alkyl, hydroxy, halo, haloalkyl, amino, alkylamino, dialkylamino, carboxy, alkoxy, and alkoxycarbonyl; and wherein the 6-membered heterocyclyl is attached to R either through a carbon atom or through a nitrogen atom²The carbonyl carbon of (a);

R³is hydrogen, OH, -Y-PEG-R⁷or-OC (═ O) R⁶Wherein

Y is a covalent bond or a linker;

R⁶selected from the group consisting of: unsubstituted C_1-12Alkyl, unsubstituted C_2-12Alkenyl, unsubstituted C_2-12Alkynyl, -CH₂-O-(CH₂CH₂O)_m-R⁷、-O-(CH₂CH₂O)_n-R⁷、-NH(CH₂CH₂O)_p-R⁷Phenyl, benzyl, phenethyl, pyridyl, cycloalkyl, (cycloalkyl) alkyl, cycloalkenyl, (cycloalkenyl) alkyl, 6-membered heterocycle and (5-or 6-membered heterocycle) alkyl, wherein the phenyl, pyridyl, cycloalkyl, cycloalkenyl and heterocycle moieties are optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of: alkyl, hydroxy, halo, haloalkyl, amino, alkylamino, dialkylamino, carboxy, alkoxy, and alkoxycarbonyl; and wherein the 6-membered heterocyclyl is connected to the carbonyl carbon through a carbon atom or through a nitrogen atom;

Provided that when Z is C (═ O), R³is-OC (═ O) R⁶；

PEG is one ethylene oxide unit or oligomer having two or more ethylene oxide subunits;

R⁷selected from the group consisting of: hydrogen, C_1-6Alkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl, any of which groups is optionally substituted;

R⁴selected from the group consisting of: hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl and (cycloalkyl) alkyl, said groupsAny one of which is optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of: hydroxy, halo, haloalkyl, amino, alkylamino, dialkylamino, carboxy, alkoxy, and alkoxycarbonyl;

m is an integer between 1 and 9;

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

With the proviso that R²And R³At least one of which is-C (═ O) R, respectively⁵and-OC (═ O) R⁶(ii) a The precondition is as follows:

1) said compound is not

2) When R is¹Is unsubstituted alkyl, R³Is hydrogen and R⁴When it is unsubstituted alkyl, then R⁵Is not optionally substituted phenyl or optionally substituted pyridyl,

3) when R is¹Is unsubstituted alkyl, R⁴Is unsubstituted alkyl and R ³is-OC (═ O) R⁶Then R⁵And R⁶Are not all optionally substituted pyridyl, or

4) Said compound is not

2. The compound of claim 1, having formula II:

or a pharmaceutically acceptable salt or solvate thereof.

3. The compound of claim 1 or 2, having formula III:

or a pharmaceutically acceptable salt or solvate thereof, wherein R¹、R²、R³And R⁴As defined in claim 1.

4. The compound of claim 1 or 2, having formula IV:

or a pharmaceutically acceptable salt or solvate thereof, wherein R¹、R⁴And R⁵As defined in claim 1, and R³¹Is hydrogen or OH.

5. The compound of claim 1 or 2, having formula V:

or a pharmaceutically acceptable salt or solvate thereof, wherein R¹、R⁴And R⁵As defined in claim 1.

6. The compound of claim 1, having formula VI:

or a pharmaceutically acceptable salt or solvate thereof, wherein R¹And R⁴As defined in claim 1, and R³is-OC (═ O) R⁶Wherein R is⁶As defined in claim 1.

7. Such asThe compound of any one of claims 1-6, or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹Is H or alkyl optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of: hydroxyl, halo, haloalkyl, amino, alkylamino, dialkylamino, carboxyl, alkoxy, and alkoxycarbonyl.

8. The compound of claim 7, or a pharmaceutically acceptable salt or solvate thereof, wherein R¹Is H or unsubstituted C_1-6An alkyl group.

9. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt or solvate thereof, wherein R¹is-PEG-R⁷Wherein R is⁷As defined in claim 1, and PEG is- (CH)₂CH₂O)_q-, wherein q varies from 1 to 50.

10. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt or solvate thereof, wherein R¹Is PG and the PG is selected from the group consisting of: methyl, tert-butyl, optionally substituted benzyl, optionally substituted benzoyl, acetyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl and triisopropylsilyl.

11. The compound of any one of claims 1-3 and 7-10, or a pharmaceutically acceptable salt or solvate thereof, wherein R ³Is hydrogen.

12. The compound of any one of claims 1-3 and 7-10, or a pharmaceutically acceptable salt or solvate thereof, wherein R³Is OH.

13. The compound of any one of claims 1-3 and 7-10, or a pharmaceutically acceptable salt thereof, wherein R³is-Y-PEG-R⁷And R is²is-C (═ O) R⁵Wherein Y, PEG, R⁷And R⁵As defined in claim 1.

14. The compound of any one of claims 1-3 and 7-10, or a pharmaceutically acceptable salt or solvate thereof, wherein R³is-OC (═ O) R⁶Wherein R is⁶As defined in claim 1.

15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt or solvate thereof, wherein R⁴Is unsubstituted C_1-6An alkyl group.

16. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt or solvate thereof, wherein R⁴Is methyl.

17. The compound of any one of claims 6 and 14-16, or a pharmaceutically acceptable salt or solvate thereof, wherein R⁶Is unsubstituted C_1-6Alkyl, with the proviso that the compound is not

18. The compound of claim 6 or 17, or a pharmaceutically acceptable salt or solvate thereof, wherein R⁶Is methyl, with the proviso that the compound is not

19. The compound of any one of claims 6 and 14-16, or a pharmaceutically acceptable salt or solvate thereof, wherein R⁶Is unsubstituted C_7-12An alkyl group.

20. The compound of any one of claims 1-5 and 7-19, or a pharmaceutically acceptable salt or solvate thereof, wherein R⁵Is unsubstituted C_1-6An alkyl group.

21. The compound of any one of claims 1-5 and 7-19, or a pharmaceutically acceptable salt or solvate thereof, wherein R⁵Is unsubstituted C_7-12An alkyl group.

22. The compound of any one of claims 1-5 and 7-19, or a pharmaceutically acceptable salt or solvate thereof, wherein R⁵is-CH₂-O-(CH₂CH₂O)_m-CH₃Wherein m is 1, 2 or 3.

23. The compound of any one of claims 1-3, 6-10, and 14-16, or a pharmaceutically acceptable salt or solvate thereof, wherein R⁶is-CH₂-O-(CH₂CH₂O)_m-CH₃Wherein m is 1, 2 or 3.

24. The compound of claim 4, wherein R³¹Is OH.

25. A compound according to claim 2, or a pharmaceutically acceptable salt or solvate thereof, wherein

R¹Is H or unsubstituted C_1-6An alkyl group;

R²is-C (O) (C)_1-6) An alkyl group;

R³is H or OH; and is

R⁴Is unsubstituted C_1-6An alkyl group, a carboxyl group,

with the proviso that said compound is not

26. The compound of claim 4, having formula IV:

Or a pharmaceutically acceptable salt or solvate thereof, wherein

R¹Is H; c optionally substituted by 1, 2 or 3 substituents_1-6Alkyl, each of said substituents being independently selected from the group consisting of: hydroxy, halo (C)_1-4) Alkyl, amino, C_1-4Alkylamino radical, di (C)_1-4) Alkylamino, carboxyl, C_1-4Alkoxy and C_1-4An alkoxycarbonyl group; or-PEG-R⁷；

R³¹Is hydrogen or OH;

R⁴selected from the group consisting of: hydrogen, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl and (C)_3-6Cycloalkyl) (C)_1-4) Alkyl, any of said groups being optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of: hydroxy, halo (C)_1-4) Alkyl, amino, C_1-4Alkylamino radical, di (C)_1-4) Alkylamino, carboxyl, C_1-4Alkoxy and C_1-4An alkoxycarbonyl group;

R⁵selected from the group consisting of: unsubstituted C_1-12Alkyl, unsubstituted C_2-12Alkenyl, unsubstituted C_2-12Alkynyl, -CH₂-O-(CH₂CH₂O)_m-R⁷、-O-(CH₂CH₂O)_n-R⁷and-NH- (CH)₂CH₂O)^p-R⁷；

R⁷Selected from the group consisting of: hydrogen and C_1-6An alkyl group;

m is an integer between 1 and 9;

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

PEG is an ethylene oxide unit or oligomer having from 2 to about 10 ethylene oxide subunits, with the proviso that the compound is not

27. The compound of claim 26, or a pharmaceutically acceptable salt or solvate thereof, wherein R¹Is H or unsubstituted C_1-6Alkyl, and R⁴Is unsubstituted C_1-6An alkyl group.

28. The compound of claim 26 or 27, or a pharmaceutically acceptable salt thereof, wherein R³¹Is OH.

29. The compound of any one of claims 26-28, or a pharmaceutically acceptable salt or solvate thereof, wherein R¹And R⁴Is methyl.

30. The compound of any one of claims 26-29, or a pharmaceutically acceptable salt thereof, wherein R⁵Is unsubstituted C_1-6An alkyl group.

31. The compound of any one of claims 26-30, or a pharmaceutically acceptable salt thereof, wherein R⁵Is methyl.

32. The compound of any one of claims 26-29, or a pharmaceutically acceptable salt thereof, wherein R⁵Is unsubstituted C_7-12An alkyl group.

33. The compound of any one of claims 26-29 and 32, or a pharmaceutically acceptable salt thereof, wherein R⁵Is unsubstituted heptyl, octyl or nonyl.

34. The method of any one of claims 26-29 and 32A compound or a pharmaceutically acceptable salt thereof, wherein R⁵Is unsubstituted decyl, undecyl or dodecyl.

35. The compound of claim 34, or a pharmaceutically acceptable solvate thereof, wherein R⁵Is an undecyl group.

36. The compound of any one of claims 26-29, or a pharmaceutically acceptable salt thereof, wherein

R⁵Selected from the group consisting of: -CH₂-O-(CH₂CH₂O)_m-R⁷、-O-(CH₂CH₂O)_n-R⁷and-NH- (CH)₂CH₂O)_p-R⁷；

R⁷Is hydrogen or C_1-4An alkyl group;

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.

37. The compound of any one of claims 26-29 and 36, or a pharmaceutically acceptable salt thereof, wherein R⁷Is hydrogen or methyl.

38. The compound of any one of claims 26-29 and 36, or a pharmaceutically acceptable salt thereof, wherein R⁵is-CH₂-O-(CH₂CH₂O)_m-R⁷。

39. The compound of any one of claims 26-29 and 36-38, or a pharmaceutically acceptable salt thereof, wherein m is 1, 2, or 3.

40. The compound of claim 39, or a pharmaceutically acceptable salt thereof, wherein m is 2.

41. The compound of any one of claims 38-40 or a compound thereofA pharmaceutically acceptable salt or solvate thereof, wherein R⁷Is methyl.

42. The compound of any one of claims 2 and 26-31, which is

Or a pharmaceutically acceptable salt or solvate thereof.

43. The compound of claim 42, which is

Or a pharmaceutically acceptable salt or solvate thereof.

44. The compound of claim 26, which is

Or a pharmaceutically acceptable salt or solvate thereof.

45. The compound of claim 6, having formula VI:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

R¹is H; c optionally substituted by 1, 2 or 3 substituents_1-6Alkyl, each of said substituents being independently selected from the group consisting of: hydroxy, halo (C)_1-4) Alkyl, amino, C_1-4Alkylamino radical, di (C)_1-4) An alkylamino group, a carboxyl group,C_1-4Alkoxy and C_1-4An alkoxycarbonyl group; or-PEG-R⁷；

R⁴Selected from the group consisting of: hydrogen, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl and (C)_3-6Cycloalkyl) (C)_1-4) Alkyl, any of said groups being optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of: hydroxy, halo (C)_1-4) Alkyl, amino, C_1-4Alkylamino radical, di (C)_1-4) Alkylamino, carboxyl, C_1-4Alkoxy and C_1-4An alkoxycarbonyl group;

R³is-OC (═ O) R⁶Wherein R is⁶Selected from the group consisting of: unsubstituted C _1-4Alkyl, unsubstituted C_2-4Alkenyl, unsubstituted C_2-4Alkynyl or-CH₂-O-(CH₂CH₂O)_m-R⁷；

m is 1;

R⁷selected from the group consisting of: hydrogen and C_1-6An alkyl group; and is

PEG is one ethylene oxide unit or oligomer having 2 to about 10 ethylene oxide subunits,

with the proviso that said compound is not

46. The compound of claim 45, or a pharmaceutically acceptable salt or solvate thereof, wherein R⁶Is methyl or ethyl.

47. The compound of claim 45 or claim 46, or a pharmaceutically acceptable salt or solvate thereof, wherein R¹Is H or unsubstituted C_1-6Alkyl, and R⁴Is unsubstituted C_1-6An alkyl group.

48. The compound of any one of claims 45-47, or a pharmaceutically acceptable salt or solvate thereof, wherein R₁And R⁴Is methyl.

49. The compound of claim 2, having formula II:

a pharmaceutically acceptable salt or solvate thereof, wherein:

R¹is H; c optionally substituted by 1, 2 or 3 substituents_1-6Alkyl, each of said substituents being independently selected from the group consisting of: hydroxy, halo (C)_1-4) Alkyl, amino, C_1-4Alkylamino radical, di (C)_1-4) Alkylamino, carboxyl, C_1-4Alkoxy and C_1-4An alkoxycarbonyl group; or-PEG-R ⁷；

R²is-C (═ O) R⁵And R is³is-OC (═ O) R⁶Wherein

R⁵And R⁶Are the same or different and are selected from the group consisting of: straight-chain unsubstituted C_7-9Alkyl, straight-chain unsubstituted C_7-9Alkenyl, straight-chain unsubstituted C_7-9Alkynyl, -CH₂-O-(CH₂CH₂O)_m-R⁷、-O-(CH₂CH₂O)_n-R⁷and-NH- (CH)₂CH₂O)_p-R⁷；

R⁷Selected from the group consisting of: hydrogen and C_1-6An alkyl group;

m is 2 or 3;

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

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

50. The compound of claim 49, or a pharmaceutically acceptable salt or solvate thereof, wherein R⁵And R⁶Each independently selected from the group consisting of: heptyl, octyl, nonyl, -CH₂-O-(CH₂CH₂O)_m-R⁷、-O-(CH₂CH₂O)_n-R⁷and-NH- (CH)₂CH₂O)_p-R⁷(ii) a Wherein R is⁷Is hydrogen or C_1-4An alkyl group.

51. The compound of claim 49 or 50, wherein R ⁵And R⁶Is the same, having formula V:

or a pharmaceutically acceptable salt or solvate thereof.

52. The compound of claim 51, or a pharmaceutically acceptable salt or solvate thereof, wherein R⁵is-CH₂-O-(CH₂CH₂O)_m-R⁷Wherein R is⁷Is hydrogen or methyl.

53. The compound of claim 49 or 50, or a pharmaceutically acceptable salt or solvate thereof, wherein R⁵And R⁶Is different.

54. The compound of any one of claims 49-53, or a pharmaceutically acceptable salt or solvate thereof, wherein R¹Is H or unsubstituted C_1-6Alkyl, and R⁴Is unsubstituted C_1-6An alkyl group.

55. The compound of any one of claims 49-54, or a pharmaceutically acceptable salt or solvate thereof, wherein R₁And R⁴Is methyl.

56. The compound of claim 49 or 51, which is

Or a pharmaceutically acceptable salt or solvate thereof.

57. The compound of claim 2, having formula II:

a pharmaceutically acceptable salt or solvate thereof, wherein:

R¹is H; c optionally substituted by 1, 2 or 3 substituents_1-6Alkyl, each of said substituents being independently selected from the group consisting of: hydroxy, halo (C)_1-4) Alkyl, amino, C _1-4Alkylamino radical, di (C)_1-4) Alkylamino, carboxyl, C_1-4Alkoxy and C_1-4An alkoxycarbonyl group; or-PEG-R⁷；

R⁴Selected from the group consisting of: hydrogen, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl and (C)_3-6Cycloalkyl) (C)_1-4) Alkyl, any of said groups being optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of:hydroxy, halo (C)_1-4) Alkyl, amino, C_1-4Alkylamino radical, di (C)_1-4) Alkylamino, carboxyl, C_1-4Alkoxy and C_1-4An alkoxycarbonyl group;

R²is-C (═ O) R⁵And R is³is-OC (═ O) R⁶Wherein

R⁵And R⁶Are the same or different and are selected from the group consisting of: straight-chain unsubstituted C_10-12Alkyl, straight-chain unsubstituted C_10-12Alkenyl, straight-chain unsubstituted C_10-12Alkynyl, -CH₂-O-(CH₂CH₂O)_m-R⁷、-O-(CH₂CH₂O)_n-R⁷and-NH- (CH)₂CH₂O)_p-R⁷；

R⁷Selected from the group consisting of: hydrogen and C_1-6An alkyl group;

m is an integer between 4 and 9;

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

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

58. The compound of claim 57, or a pharmaceutically acceptable salt or solvate thereof, wherein R⁵And R⁶Each independently selected from the group consisting of: decyl, undecyl and dodecyl.

59. The compound of claim 57 or 58, wherein R⁵And R⁶Is the same, having formula V:

or a pharmaceutically acceptable salt or solvate thereof.

60. The compound of claim 59 or pharmaceutically acceptable thereofA salt or solvate thereof, wherein R⁵Is an undecyl group.

61. The compound of claim 57 or 58, or a pharmaceutically acceptable salt or solvate thereof, wherein R⁵And R⁶Is different.

62. The compound of any one of claims 57-61, or a pharmaceutically acceptable salt or solvate thereof, wherein R¹Is H or unsubstituted C_1-6Alkyl, and R⁴Is unsubstituted C_1-6An alkyl group.

63. The compound of any one of claims 57-62, or a pharmaceutically acceptable salt or solvate thereof, wherein R₁And R⁴Is methyl.

64. The compound of claim 57 or 59, which is

Or a pharmaceutically acceptable salt or solvate thereof.

65. The compound of claim 6, having formula VI:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

R¹is H; c optionally substituted by 1, 2 or 3 substituents_1-6Alkyl, each of said substituents being independently selected from the group consisting of: hydroxy, halo (C) _1-4) Alkyl, amino, C_1-4Alkylamino radical, di (C)_1-4) Alkylamino, carboxyl, C_1-4Alkoxy and C_1-4An alkoxycarbonyl group; or-PEG-R⁷；

R³is-OC (═ O) R⁶Wherein R is⁶Selected from the group consisting of: straight-chain unsubstituted C_10-12Alkyl, straight-chain unsubstituted C_10-12Alkenyl, straight-chain unsubstituted C_10-12Alkynyl, -CH₂-O-(CH₂CH₂O)_m-R⁷、-O-(CH₂CH₂O)_n-R⁷and-NH- (CH)₂CH₂O)_p-R⁷；

R⁷Selected from the group consisting of: hydrogen and C_1-6An alkyl group;

m is an integer between 4 and 9;

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

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

66. The compound of claim 65, or a pharmaceutically acceptable salt or solvate thereof, wherein R⁶Is decyl, undecyl or dodecyl.

67. The compound of claim 65 or claim 66, or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹Is H or unsubstituted C_1-6Alkyl, and R⁴Is unsubstituted C_1-6An alkyl group.

68. As claimed inThe compound of any one of claims 65-67, or a pharmaceutically acceptable salt or solvate thereof, wherein R⁶Is an undecyl group.

69. The compound of any one of claims 65-68, or a pharmaceutically acceptable salt or solvate thereof, wherein R₁And R⁴Is methyl.

70. The compound of claim 65, which is

Or a pharmaceutically acceptable salt or solvate thereof.

71. The compound of claim 1, which is

Or a pharmaceutically acceptable salt or solvate thereof.

72. A pharmaceutical composition comprising a compound of formula I:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

R¹is H; alkyl optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of: hydroxy, halo, haloalkyl, amino, alkylamino, dialkylamino, carboxy, alkoxy, and alkoxycarbonyl; -PEG-R⁷(ii) a Or a hydroxyl protecting group PG selected from the group consisting of: alkyl, arylalkyl, heterocyclyl, (heterocyclyl) alkyl, acyl, silyl and carbonate groups, any of said groups optionally being substituted Substitution;

z is C-OR²Or C (═ O);

is a single or double bond, with the proviso that when Z is C (═ O),is a single bond, and when Z is C-OR²When the temperature of the water is higher than the set temperature,is a double bond;

R²is-C (═ O) R⁵or-PEG-R⁷Wherein

R⁵Selected from the group consisting of: unsubstituted C_1-12Alkyl, unsubstituted C_2-12Alkenyl, unsubstituted C_2-12Alkynyl, -CH₂-O-(CH₂CH₂O)_m-R⁷、-O-(CH₂CH₂O)_n-R⁷、-NH-(CH₂CH₂O)_p-R⁷Phenyl, benzyl, phenethyl, pyridyl, cycloalkyl, (cycloalkyl) alkyl, cycloalkenyl, (cycloalkenyl) alkyl, 6-membered heterocycle and (5-or 6-membered heterocycle) alkyl, wherein the phenyl, pyridyl, cycloalkyl, cycloalkenyl and heterocycle moieties are optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of: alkyl, hydroxy, halo, haloalkyl, amino, alkylamino, dialkylamino, carboxy, alkoxy, and alkoxycarbonyl; and wherein the 6-membered heterocyclyl is attached to R either through a carbon atom or through a nitrogen atom²The carbonyl carbon of (a);

R³is hydrogen, OH, -Y-PEG-R⁷or-OC (═ O) R⁶Wherein

Y is a covalent bond or a linker;

Provided that when Z is C (═ O), R³is-OC (═ O) R⁶；

PEG is one ethylene oxide unit or oligomer having two or more ethylene oxide subunits;

R⁷selected from the group consisting of: hydrogen, C_1-6Alkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl, any of which groups is optionally substituted;

R⁴selected from the group consisting of: hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl and (cycloalkyl) alkyl, any of which is optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of: hydroxy, halo, haloalkyl, amino, alkylamino, dialkylamino, carboxy, alkoxy, and alkoxycarbonyl;

m is an integer between 1 and 9;

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

With the proviso that R²And R³At least one of which is-C (═ O) R, respectively⁵and-OC (═ O) R⁶(ii) a The precondition is as follows:

1) said compound is not

2) When R is¹Is unsubstituted alkyl, R³Is hydrogen and R⁴When it is unsubstituted alkyl, then R⁵Is not optionally substituted phenyl or optionally substituted pyridyl,

3) when R is¹Is unsubstituted alkyl, R⁴Is unsubstituted alkyl and R ³is-OC (═ O) R⁶Then R⁵And R⁶Are not all optionally substituted pyridyl groups,

4) said compound is not

And one or more pharmaceutically acceptable carriers.

73. The pharmaceutical composition of claim 72, further comprising at least one parent opioid.

74. The pharmaceutical composition of claim 73, about 0.1 wt% to about 30 wt% of the at least one parent opioid.

75. The pharmaceutical composition of any one of claims 72-74, wherein the composition is formulated for an oral dosage form.

76. The pharmaceutical composition of claim 72, comprising a compound of any one of claims 1-71, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carriers.

77. A composition comprising one or more compounds of any one of claims 1-71, or a pharmaceutically acceptable salt or solvate thereof, and at least one parent opioid.

78. The composition of claim 77, comprising about 0.1 wt% to about 30 wt% of the at least one parent opioid.

79. The composition of claim 77 or 78, comprising about 1 wt% to about 20 wt% of the at least one parent opioid.

80. The composition of any one of claims 77-79, wherein the at least one parent opioid is oxycodone.

81. An oral formulation comprising a therapeutically effective amount of the composition of any one of claims 77-80.

82. A composition comprising one or more compounds of any one of claims 26-56, or a pharmaceutically acceptable salt or solvate thereof, and at least one parent opioid.

83. The composition of claim 82, comprising about 0.1 wt% to about 30 wt% of the at least one parent opioid.

84. The composition of claim 82 or 83, comprising about 1 wt% to about 20 wt% of the at least one parent opioid.

85. The composition of any one of claims 82-84, wherein the at least one parent opioid is oxycodone.

86. An oral formulation comprising a therapeutically effective amount of the composition of any one of claims 82-85.

87. A method of treating or preventing a disorder responsive to modulation of one or more opioid receptors in a patient, comprising administering to the patient in need of such treatment or prevention an effective amount of a compound of formula I:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

z is C-OR²Or C (═ O);

is a single or double bond, with the proviso that when Z is C (═ O),

R²is-C (═ O) R⁵or-PEG-R⁷Wherein

R⁵Selected from the group consisting of: unsubstituted C_1-12Alkyl, unsubstituted C_2-12Alkenyl, unsubstituted C_2-12Alkynyl, -CH₂-O-(CH₂CH₂O)_m-R⁷、-O-(CH₂CH₂O)_n-R⁷、-NH-(CH₂CH₂O)_p-R⁷Phenyl, benzyl, phenethyl, pyridyl, cycloalkyl, (cycloalkyl) alkyl, cycloalkenyl, (cycloalkenyl) alkyl, 6-membered heterocycle and (5-or 6-membered heterocycle) alkyl, wherein the phenyl, pyridyl, cycloalkyl, cycloalkenyl and heterocycle moieties are optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of: alkyl, hydroxy, halo, haloalkyl, amino, alkylamino, dialkylamino, carboxy, alkoxy, and alkoxycarbonyl; and wherein the 6-membered heterocyclyl is attached to R either through a carbon atom or through a nitrogen atom ²The carbonyl carbon of (a);

R³is hydrogen, OH, -Y-PEG-R⁷or-OC (═ O) R⁶Wherein

Y is a covalent bond or a linker;

provided that when Z is C (═ O), R³is-OC (═ O) R⁶；

PEG is one ethylene oxide unit or oligomer having two or more ethylene oxide subunits;

R⁷selected from the group consisting of: hydrogen, C_1-6Alkyl, aryl, heteroarylCycloalkyl and heterocyclyl, any of which groups is optionally substituted;

m is an integer between 1 and 9;

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

With the proviso that R²And R³At least one of which is-C (═ O) R, respectively⁵and-OC (═ O) R⁶(ii) a The precondition is as follows:

1) said compound is not

2) When R is¹Is unsubstituted alkyl, R³Is hydrogen and R⁴When it is unsubstituted alkyl, then R⁵Is not optionally substituted phenyl or optionally substituted pyridyl,

3) when R is¹Is unsubstituted alkyl, R4 is unsubstituted alkyl and R³is-OC (═ O) R⁶Then R⁵And R⁶Are not all optionally substituted pyridyl groups,

4) said compound is not

88. The method of claim 87, comprising administering to the patient in need of such treatment or prevention an effective amount of a compound of any one of claims 1-71, or a pharmaceutically acceptable salt or solvate thereof.

89. The method of claim 87 or 88, wherein the condition is pain.

90. The method of claim 87 or 88, wherein the disorder is constipation, diarrhea, alcohol addiction withdrawal, or drug addiction withdrawal.

91. A method of treating, ameliorating, or preventing pain, constipation, diarrhea, alcohol addiction withdrawal, or drug addiction withdrawal in a patient, comprising administering to the patient in need of such treatment or prevention an effective amount of a compound of any one of claims 1-71, or a pharmaceutically acceptable salt or solvate thereof.

92. The method of claim 91, wherein the method is for treating pain.

93. The method of claim 92, wherein the pain is acute pain, chronic pain, or surgical pain.

94. The method of claim 93, wherein the pain is chronic pain.

95. The method of claim 94, wherein the chronic pain is neuropathic pain, post-surgical pain, or inflammatory pain.

96. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt or solvate of any one of claims 1-71 for use in treating a disorder responsive to modulation of one or more opioid receptors.

97. A compound of any one of claims 1-71, or a pharmaceutically acceptable salt or solvate thereof, for use in treating a disorder responsive to modulation of one or more opioid receptors.

98. A process for preparing a pharmaceutical composition comprising mixing a compound of any one of claims 1-71, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

99. A kit comprising a container containing an effective amount of a compound of any one of claims 1-71, or a pharmaceutically acceptable salt or solvate thereof, and instructions for therapeutic use.

100. A method of slowing the onset of opioid activity in a mammal in need of opioid therapy, comprising orally administering to the mammal a therapeutically effective amount of a compound or mixture of compounds of any one of claims 1-71, or a pharmaceutically acceptable salt or solvate thereof.

101. The method of claim 100, comprising orally administering a compound or mixture of compounds having formula V:

or a pharmaceutically acceptable salt or solvate thereof, wherein

R¹Is H or unsubstituted C_1-6An alkyl group;

R⁴is unsubstituted C_1-6An alkyl group; and is

R⁵Is decyl, undecyl or dodecyl.

102. The method as recited in claim 101, wherein R¹Is H or methyl, and R⁴Is methyl.

103. As claimed in claim 101 or claimThe method of claim 102, wherein R⁵Is an undecyl group.

104. The method of any one of claims 101-103, further comprising co-administering one or more additional therapeutic agents.

105. The method of claim 104, wherein the one or more additional therapeutic agents is one or more non-steroidal anti-inflammatory agents.

106. The method of claim 104, wherein the one or more additional therapeutic agents is one or more opioid agonists.

107. The method of claim 104, wherein the one or more additional therapeutic agents is one or more opioid antagonists.

108. The method of any one of claims 101-103, wherein the compound or mixture of compounds is administered in a single dosage form further comprising an effective amount of the parent opioid.

109. A method of treating, ameliorating or preventing constipation, diarrhea, alcohol addiction withdrawal or drug addiction withdrawal in a patient, comprising administering to the patient in need of such treatment or prevention an effective amount of a compound of any one of claims 65-70, or a pharmaceutically acceptable salt or solvate thereof.

110. The compound of any one of claims 65-70, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment, amelioration or prevention of constipation, diarrhea, alcohol addiction withdrawal, or drug addiction withdrawal.

Technical Field

The invention belongs to the field of pharmaceutical chemistry. In particular, the present invention relates to novel opioid compounds.

RELATED ART

The primary site of pain control is in the Central Nervous System (CNS). The three major classes of opioid receptors, μ (mu), κ (kappa) and (delta), are distributed throughout The CNS and peripheral regions (Foss, J.F., The American journal Surgery 182 (11.2001): 19S-26S (2001)). The major receptor involved in pain management is the μ opioid receptor (Foss, j.f., supra).

Opioids (also known as opioid agonists) are a group of compounds that bind to the opioid receptors mentioned above and exhibit opioid or morphine-like properties. Opioids are widely administered for a variety of medical indications, but they are mainly used as moderate to strong analgesics. Examples of opioid compounds include, but are not limited to, morphine, oxycodone, hydromorphone, oxymorphone, hydrocodone, levorphanol (levophanol), methadone, meperidine, fentanyl, codeine, propoxyphene, buprenorphine, butorphanol, pentazocine, and nalbuphine.

The use of opioid compounds has been reported to have a number of potential side effects, including abuse and metastasis.

Attempts have been made to reduce the abuse potential of opioids. For example, various opioid receptor antagonists have been developed to block the effects of opioid agonists when overdosed. Additionally, in an attempt to formulate abuse resistant tablets, various formulations have been developed containing an opioid receptor agonist in combination with an opioid antagonist, wherein the antagonist becomes substantially bioavailable upon crushing or tampering with the tablet.

Other alternatives to reduce the abuse potential of opioids include the use of opioid prodrugs. Opioid prodrugs can exhibit pharmacological properties different from those of opioids, such as those associated with absorption, distribution, and elimination. For example, U.S. patent No. 7,230,005 describes the conversion of an opiate analgesic into its poorly absorbed ester prodrug or other prodrug derivative; U.S. patent application publication No. 2008/0318905 describes covalently linking a prodrug moiety to an amine functional group of an abuse-susceptible parent drug; U.S. patent application publication No. 2009/0192095 describes opioid prodrugs comprising an opioid analgesic covalently bonded through a carbamate linkage to a peptide 1-5 amino acids long; WO 2011/002991 a1 describes hydrocodone enol-ester conjugates as prodrugs; U.S. patent application publication No. 2017/095734 describes hydrocodone and hydromorphone prodrugs; U.S. patent application publication No. 2017/015266 describes oxycodone prodrugs; and U.S. patent application publication No. 2017/0151228 describes oxymorphone prodrugs.

There remains a need to provide opioid prodrugs that, when administered to a patient in established need thereof, provide effective analgesia while reducing the potential for abuse or adverse side effects.

Background

Disclosure of Invention

In one aspect, the present disclosure provides compounds represented by formulas I, II, III, IV, V, and VI below, and pharmaceutically acceptable salts and solvates thereof, which are collectively referred to herein as "disclosed compounds" (each of which is hereinafter referred to individually as "the disclosed compounds").

In another aspect, the present disclosure provides the use of a compound of the present disclosure as a modulator of one or more opioid receptors. In particular, the present disclosure provides for the use of compounds of the present disclosure as modulators of μ, κ and/or ORL-1 opioid receptors, and in particular as modulators of μ opioid receptors.

In another aspect, the present disclosure provides a method of treating, ameliorating, or preventing a disorder responsive to modulation of one or more opioid receptors in a patient, comprising administering to the patient an effective amount of a compound of the present disclosure.

In another aspect, the present disclosure provides the use of a compound of the present disclosure as an analgesic for treating, ameliorating, or preventing pain.

The present invention further provides a method of treating, ameliorating or preventing pain comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present disclosure. In certain embodiments, the pain is acute pain, chronic pain (including but not limited to neuropathic pain, post-operative pain, and inflammatory pain), and surgical pain. In certain embodiments, the compounds of the present disclosure are useful for treating or preventing chronic pain. In a particular embodiment, said administration is by oral route. In one embodiment, the compound is formulated in a solid oral dosage form. In another embodiment, the compound is formulated in a liquid oral dosage form. In one embodiment, the dosage form is designed for immediate release. In another embodiment, the dosage form is designed for controlled release.

In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure and one or more pharmaceutically acceptable carriers. Such compositions are useful for treating, ameliorating, or preventing pain in a patient. In a particular embodiment, the pharmaceutical composition is an oral dosage form. In one embodiment, the pharmaceutical composition is a solid oral dosage form. In another embodiment, the pharmaceutical composition is a liquid oral dosage form. In one embodiment, the dosage form is designed for immediate release. In another embodiment, the dosage form is designed for controlled release.

In another embodiment, the present invention relates to a method of treating, ameliorating or preventing pain comprising administering to a patient in need of such treatment, amelioration or prevention a pharmaceutical composition of the present invention. In a particular embodiment, said administration is by oral route. In one embodiment, the compound is in a solid oral dosage form. In another embodiment, the compound is in a liquid oral dosage form. In one embodiment, the dosage form is designed for immediate release. In another embodiment, the dosage form is designed for controlled release.

In another aspect, the present disclosure provides compounds of the present disclosure for use in treating, ameliorating, or preventing a disorder responsive to modulation of one or more opioid receptors. Preferably, the disorder is responsive to modulation of the mu opioid receptor.

In another aspect, the present disclosure provides a method of modulating one or more opioid receptors in a patient in need of such modulation, comprising administering to the patient an effective amount of a compound of the present disclosure.

In another aspect, the present disclosure provides a compound of the present disclosure for use in treating, ameliorating or preventing pain in a patient in need thereof.

In another aspect, the present disclosure provides compounds of the present disclosure for treating, ameliorating or preventing pain, such as acute pain, chronic pain (including but not limited to neuropathic pain, post-operative pain, and inflammatory pain), or surgical pain, in a patient.

In another aspect, the present disclosure provides the use of a compound of the present disclosure in the manufacture of a medicament for treating, ameliorating, or preventing a disorder responsive to modulation of one or more opioid receptors.

In another aspect, the present disclosure provides the use of a compound of the present disclosure in the manufacture of a medicament for modulating one or more opioid receptors in a patient. Preferably, mu or kappa opioid receptors are modulated.

In another aspect, the present disclosure provides compounds of the present disclosure for use as a medicament.

In another aspect, the present disclosure provides the use of a compound of the present disclosure in the manufacture of a medicament for treating, ameliorating, or preventing pain, such as acute pain, chronic pain, or surgical pain, in a patient.

In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure for use in treating, ameliorating, or preventing a disorder responsive to modulation of one or more opioid receptors.

The present disclosure further provides a process for preparing a pharmaceutical composition comprising mixing a compound of the present disclosure and a pharmaceutically acceptable carrier to form the pharmaceutical composition.

In another aspect, the invention relates to a kit comprising a sterile container containing an effective amount of a compound of the disclosure and instructions for therapeutic use.

In another aspect, the present disclosure further provides a method of reducing the onset of opioid activity in a mammal in need of opioid therapy, comprising orally administering to the mammal a therapeutically effective amount of a compound of the present disclosure or a mixture of compounds of the present disclosure. In one embodiment of this aspect of the disclosure, the compounds of the present disclosure are co-administered with one or more other therapeutic agents. In another embodiment, the method provides for slowing the onset of analgesic activity of the opioid.

Additional embodiments and advantages of the present disclosure will be set forth in part in the description which follows, and in part will be derived from the description, or may be learned by practice of the present disclosure. The embodiments and advantages of the disclosure will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims.

It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention as claimed.

Drawings

The following drawings are given by way of illustration only and are therefore not intended to limit the scope of the invention.

FIG. 1A, FIG. 1B, FIG. 1C and FIG. 1D show the COSY NMR spectrum, part of the 6-acetyl oxycodone prepared in example 1, respectively¹H NMR spectrum,¹H NMR spectrum and HPLC chromatogram.

FIGS. 2A and 2B respectively show the preparation of 6-PEG oxycodone in example 2¹H NMR spectrum and HPLC chromatogram.

FIGS. 3A and 3B show the preparation of 6, 14-bis-lauroyl oxycodone prepared in example 3, respectively¹H NMR spectrum and HPLC chromatogram.

FIGS. 4A and 4B respectively show the preparation of 6-lauroyl oxycodone in example 4¹H NMR spectrum and HPLC chromatogram.

FIGS. 5A and 5B show the preparation of 6, 14-bis-valeryl oxycodone prepared in example 5, respectively¹H NMR spectrum and HPLC chromatogram.

FIG. 6 shows the results of the hydrolysis of 6-acetyl oxycodone in different media as set forth in example 6.

FIGS. 7A and 7B show the preparation of 6, 14-bis-acetyl oxycodone prepared in example 7, respectively¹H NMR spectrum and HPLC chromatogram.

FIG. 8 shows the results of the hydrolysis of 6-acetylhydrocodone in various media as set forth in example 9.

Figure 9 shows the results of the hydrolysis of 6, 14-bis-PEG-oxycodone in different media as set forth in example 11.

FIG. 10 shows an RP flash chromatogram obtained for the separation of 14-lauroyl oxycodone from a mixture of 6, 14-bis-lauroyl oxycodone and 14-lauroyl oxycodone as described in example 14.

FIG. 11 shows an RP flash chromatogram obtained for the purification of 14-lauroyl oxycodone from a mixture of 14-lauroyl oxycodone and oxycodone as described in example 14.

Detailed Description

One aspect of the present invention provides a compound of the present disclosure represented by formula I:

and pharmaceutically acceptable salts and solvates thereof, wherein:

z is C-OR²Or C (═ O);

Is a single or double bond, with the proviso that when Z is C (═ O),is a single bond, and when Z is C-OR²When the temperature of the water is higher than the set temperature,

is a double bond;

R²is-C (═ O) R⁵or-PEG-R⁷Wherein

R⁵Selected from the group consisting of: unsubstituted C_1-12Alkyl, unsubstituted C_2-12Alkenyl, unsubstituted C_2-12Alkynyl, -CH₂-O-(CH₂CH₂O)_m-R⁷、-O-(CH₂CH₂O)_n-R⁷、-NH-(CH₂CH₂O)_p-R⁷Phenyl, benzyl, phenethyl, pyridyl, cycloalkyl, (cycloalkyl) alkyl, cycloalkenyl, (cycloalkenyl) alkyl, 6-membered heterocycle and (5-or 6-membered heterocycle) alkyl, wherein the phenyl, pyridyl, cycloalkyl, cycloalkenyl and heterocycle moieties are optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of: alkyl, hydroxy, halo, haloalkyl, amino, alkylamino, dialkylamino, carboxy, alkoxy, and alkoxycarbonyl; and wherein the 6-membered heterocyclyl is attached to R either through a carbon atom or through a nitrogen atom²The carbonyl carbon of (a);

R³is hydrogen, OH, -Y-PEG-R⁷or-OC (═ O) R⁶Wherein

Y is a covalent bond or a linker;

Provided that when Z is C (═ O), R³is-OC (═ O) R⁶；

R⁷Selected from the group consisting of: hydrogen, C_1-6Alkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl, any of which groups is optionally substituted;

m is an integer between 1 and 9 (i.e., selected from 1, 2, 3, 4, 5, 6, 7, 8, and 9); and is

n and p are each independently an integer between 1 and 20 (i.e., selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20); and is

With the proviso that R²And R³At least one of which is-C (═ O) R, respectively⁵and-OC (═ O) R⁶。

In another embodiment, the compound of the present disclosure is a compound of formula II:

and pharmaceutically acceptable thereofSalts and solvates thereof, wherein R¹、R²、R³And R⁴As defined above for formula I.

In another embodiment, the compounds of the present disclosure are compounds of formula I or formula II and pharmaceutically acceptable salts and solvates thereof, with the proviso that:

1) Said compound is not

2) When R is¹Is unsubstituted alkyl, R³Is hydrogen and R⁴Is unsubstituted C_1-6When alkyl, then R⁵Is not optionally substituted phenyl or optionally substituted pyridyl; or

3) When R is¹Is unsubstituted alkyl, R⁴Is unsubstituted C_1-6Alkyl and R³is-OC (═ O) R⁶Then R⁵And R⁶Are not optionally substituted pyridyl.

In another embodiment, the compounds of the present disclosure are compounds of formula I and pharmaceutically acceptable salts and solvates thereof, with the proviso that:

4) said compound is not

In another embodiment, the compounds of the present disclosure are compounds represented by formula III:

and pharmaceutically acceptable salts and solvates thereof, wherein R¹、R²、R³And R⁴As defined for formula I.

In another embodiment, the compounds of the present disclosure are compounds represented by formula IV:

and pharmaceutically acceptable salts and solvates thereof, wherein R³¹Is hydrogen or OH, and R¹、R⁴And R⁵As defined for formula I.

In another embodiment, the compounds of the present disclosure are of formula IV and pharmaceutically acceptable salts and solvates thereof, with the proviso that:

1) said compound is not

2) When R is¹Is unsubstituted alkyl, R ³¹Is hydrogen and R⁴Is unsubstituted C_1-6When alkyl, then R⁵Is not optionally substituted phenyl or optionally substituted pyridyl.

In another embodiment, the compounds of the present disclosure are of formula I or formula II, wherein R is²is-C (═ O) R⁵，R³is-OC (═ O) R⁶And R is⁵And R⁶Is the same, represented by formula V:

and pharmaceutically acceptable salts and solvates thereof, wherein R¹、R⁴And R⁵As defined for formula I.

In another embodiment, the compounds of the present disclosure are compounds of formula V and pharmaceutically acceptable salts and solvates thereof, with the proviso that:

1) said compound is not

2) When R is¹Is unsubstituted alkyl, R⁴Is unsubstituted C_1-6When alkyl, then R⁵Is not an optionally substituted pyridyl group.

In yet another embodiment, the compounds of the present disclosure are compounds represented by formula VI:

and pharmaceutically acceptable salts and solvates thereof, wherein R³is-OC (═ O) R⁶And R is¹、R⁴And R⁶As defined for formula I.

In another embodiment, the compounds of the present disclosure are of formula VI and pharmaceutically acceptable salts and solvates thereof, with the proviso that:

4) said compound is not

In another embodiment, the compounds of the present disclosure are of any one of formulas I to VI, wherein R is ¹Is H or alkyl optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of: hydroxyl, halo, haloalkyl, amino, alkylamino, dialkylamino, carboxyl, alkoxy, and alkoxycarbonyl. In another embodiment, R¹Is H, unsubstituted C_1-10Alkyl or C substituted by 1 or 2 substituents_1-10Alkyl, each of said substituents being independently selected from the group consisting of: hydroxy, halo (C)_1-6) Alkyl, amino, (C)_1-6Alkyl) amino, di (C)_1-6) Alkylamino, carboxyl, C_1-6Alkoxy and C_1-6An alkoxycarbonyl group. In another embodiment, R¹Is H, unsubstituted C_1-6Alkyl or C substituted by 1 or 2 substituents_1-6Alkyl, each of said substituents being independently selected from the group consisting of: hydroxy, halo (C)_1-4) Alkyl, amino, (C)_1-4Alkyl radical)Amino, di (C)_1-4) Alkylamino, carboxyl, C_1-4Alkoxy and C_1-4Alkoxycarbonyl, and preferably substituted with 1 or 2 substituents each independently selected from the group consisting of: hydroxy, halo, trifluoromethyl, amino, methylamino, ethylamino, dimethylamino, diethylamino, carboxy, methoxy, ethoxy, methoxycarbonyl and ethoxycarbonyl.

In another embodiment, the compounds of the present disclosure are of any one of formulas I to VI, wherein R is¹Is H or unsubstituted C_1-6An alkyl group. In another embodiment, R¹Is H. In another embodiment, R¹Is unsubstituted C_1-4An alkyl group. In another embodiment, R¹Is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl or sec-butyl. In another embodiment, R¹Is an unsubstituted methyl group.

In another embodiment, the compounds of the present disclosure are of any one of formulas I to VI, wherein R is¹is-PEG-R⁷. As used herein, "PEG" refers to one ethylene oxide unit or oligomer having 2 or more ethylene oxide subunits. As used herein, "oligomer" refers to a molecule having from about 2 to about 50 monomers. In certain embodiments, the PEG is- (CH)₂CH₂O)_q-, wherein q varies from 1 to 50. In another embodiment, q varies from 1 to 10. In another embodiment, q varies from 1 to 5. In another embodiment, q is 1, 2, 3, 4 or 5. In another embodiment, R⁷Is hydrogen, methyl, ethyl or benzyl. In another embodiment, R ⁷Is methyl.

In another embodiment, the compounds of the present disclosure are of any one of formulas I to VI, wherein R is¹Is a hydroxyl protecting group PG selected from the group consisting of: an alkyl group, an arylalkyl group, a heterocyclic group, a (heterocyclic) alkyl group, an acyl group, a silyl group, and a carbonate group, any of which groups is optionally substituted.

In view ofIt will be apparent to those skilled in the art from this disclosure that certain groups included in the definition of PG are related to the pair R¹Such as methyl, t-butyl, etc., and thus, as described herein, includes certain groups having R that act as protecting groups for hydroxy groups¹The compounds of the present disclosure of the group may have pharmaceutical activity.

In another embodiment, the hydroxy protecting group PG is an alkyl group, typically an optionally substituted C_1-6Alkyl, and suitably unsubstituted methyl or tert-butyl.

In another embodiment, the hydroxy protecting group PG is arylalkyl. Suitable arylalkyl groups include, for example, unsubstituted benzyl, substituted benzyl, such as p-methoxybenzyl and naphthylmethyl.

In another embodiment, the hydroxy protecting group PG is a heterocyclic group, such as an unsubstituted tetrahydropyranyl or an optionally substituted tetrahydropyranyl.

In another embodiment, the hydroxyl protecting group PG is a (heterocyclyl) alkyl group. Suitable (heterocyclyl) alkyl groups include, for example, 4-morpholinyl (C)_1-4) Alkyl, such as 2- (4-morpholinyl) ethyl.

In another embodiment, the hydroxyl protecting group PG is a silyl group. The term "silyl" as used herein refers to a group having the structure:

wherein R is⁸、R⁹And R¹⁰Each independently selected from the group consisting of: alkyl, cycloalkyl, aryl, (cycloalkyl) alkyl or arylalkyl, any of which groups is optionally substituted. In one embodiment, the silyl group is a trimethylsilyl group, a tert-butyldimethylsilyl group, a tert-butyldiphenylsilyl group or a triisopropylsilyl group.

In another embodiment, the hydroxyl protecting group PG is an acyl group. The term "acyl" as used herein refers to the structure:

wherein R is¹¹Is alkyl, cycloalkyl, aryl, (cycloalkyl) alkyl or arylalkyl, any of said groups being optionally substituted. The acyl radical may be, for example, C_1-4Alkylcarbonyl (such as, for example, acetyl), arylcarbonyl (such as, for example, benzoyl), levulinyl or pivaloyl. In another embodiment, the acyl group is benzoyl.

In another embodiment, the hydroxyl protecting group is a carbonate group. The term "carbonate-based" as used herein refers to the following structure:

wherein R is¹²Is alkyl, alkenyl, cycloalkyl, aryl, (cycloalkyl) alkyl or arylalkyl, any of said groups being optionally substituted. In general, R¹²Is C_1-10Alkyl (e.g. 2, 4-dimethylpent-3-yl), C_2-6Alkenyl (e.g. vinyl or prop-2-enyl, i.e. allyl), C_3-12Cycloalkyl (e.g., adamantyl), phenyl, or benzyl. In one embodiment, the carbonate group is a benzyloxycarbonyl group.

In another embodiment, the compounds of the present disclosure are of any one of formulas I to VI, wherein R is¹Is PG, wherein the PG is selected from the group consisting of: methyl, tert-butyl, optionally substituted benzyl, optionally substituted benzoyl, acetyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl and triisopropylsilyl.

In another embodiment, the compounds of the present disclosure are of any one of formulas I to III, wherein R is³Is hydrogen and R²is-C (═ O) R⁵Wherein R is⁵As defined for formula I.

In another embodiment, the compounds of the present disclosure are of any one of formulas I to III, wherein R is ³Is OH and R²is-C (═ O) R⁵Wherein R is⁵As defined for formula I.

In another embodiment, the compounds of the present disclosure are of any one of formulas I to III, wherein R is³is-Y-PEG-R⁷And R is²is-C (═ O) R⁵Wherein Y, PEG, R⁷And R⁵As defined above for formula I.

In one embodiment, Y is a covalent bond. In another embodiment, Y is a linker. Suitable linkers include ether, amide, carbamate, amine, thioether, urea, or carbon-carbon bonds. In certain embodiments, the linker Y is selected from the group consisting of: -O-, -O-CH₂-、-CH₂-O-, -NH-, -S-, -C (═ O) O-, and-OC (═ O) -. In certain embodiments, Y is selected from the group consisting of: -O-, -O-CH₂-、-CH₂-O-and-NH-. In certain embodiments, Y is-O-. In another embodiment, R⁷Is hydrogen, methyl, ethyl or benzyl. In another embodiment, R⁷Is methyl.

In another embodiment, the compounds of the present disclosure are of any one of formulas I through III and VI, wherein R is³is-OC (═ O) R⁶Wherein R is⁶Selected from the group consisting of: unsubstituted C _1-6Alkyl, unsubstituted C_7-12Alkyl, unsubstituted C_2-6Alkenyl, unsubstituted C_2-6Alkynyl, -CH₂-O-(CH₂CH₂O)_m-CH₃、-O-(CH₂CH₂O)_n-CH₃、-NH-(CH₂CH₂O)_p-CH₃Phenyl, benzyl, phenethyl, pyridyl, cycloalkyl, (cycloalkyl) alkyl, cycloalkenyl, (cycloalkenyl) alkyl, 6-membered heterocycle and (5-or 6-membered heterocycle) alkyl, wherein the phenyl, pyridyl, cycloalkyl, cycloalkenyl and heterocycle moieties are optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of: alkyl, hydroxy, halo, haloalkyl, amino, alkylamino, dialkylamino, carboxy, alkoxy, and alkoxycarbonyl; 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; and wherein the 6-membered heterocyclic ring is attached to the carbonyl carbon through a carbon atom or through a nitrogen atom. In another embodiment, R⁶Selected from the group consisting of: unsubstituted C_1-6Alkyl, unsubstituted C_7-12Alkyl, unsubstituted C_2-6Alkenyl, unsubstituted C_2-6Alkynyl, -CH₂-O-(CH₂CH₂O)_m-CH₃、-O-(CH₂CH₂O)_n-CH₃、-NH-(CH₂CH₂O)_p-CH₃Phenyl, benzyl, phenethyl, pyridyl, C_3-6Cycloalkyl group, (C)_3-6Cycloalkyl) (C)_1-4) Alkyl radical, C_3-6Cycloalkenyl group, (C)_3-6Cycloalkenyl) (C)_1-4) Alkyl, 6-membered heterocycle and (5-or 6-membered heterocycle) (C) _1-4) Alkyl, wherein said phenyl, pyridyl, C_3-6Cycloalkyl radical, C_3-6The cycloalkenyl and heterocyclic moieties are optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of: c_1-4Alkyl, hydroxy, halo (C)_1-4) Alkyl, amino, (C)_1-4) Alkylamino radical, di (C)_1-4) Alkylamino, carboxyl, C_1-4Alkoxy and C_1-4Alkoxycarbonyl, and preferably optionally substituted with 1 or 2 substituents each independently selected from the group consisting of: methyl, hydroxy, halo, trifluoromethyl, amino, methylamino, ethylamino, dimethylamino, diethylamino, carboxy, methoxy, ethoxy, methoxycarbonyl and ethoxycarbonyl; m is 1, 2 or 3; n and p are each independently selected from the group consisting of: 1. 2, 3, 4, 5 and 6; and wherein the 6-membered heterocyclic ring is attached to the carbonyl carbon through a carbon atom.

In another embodiment, the compounds of the present disclosure are of any one of formulas I through III and VI, wherein R is³is-OC (═ O) R⁶And R is⁶Is unsubstituted C_1-6Alkyl, unsubstituted C_2-6Alkenyl or C_2-6Alkynyl. In another embodiment, R⁶Is unsubstituted C_1-4An alkyl group. In another embodiment, R ⁶Is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl or sec-butyl. In another embodiment, R⁶Is methyl. In another embodiment, R⁶Is ethyl, propyl or n-butyl.

In another embodiment, the compounds of the present disclosure are of any one of formulas I through III and VI, wherein R is³is-OC (═ O) R⁶And R is⁶Is unsubstituted C_7-12An alkyl group. In another embodiment, R⁶Is heptyl, octyl, nonyl, decyl, undecylOr dodecyl. In another embodiment, R⁶Is an undecyl group.

In another embodiment, the compounds of the present disclosure are of any one of formulas I through III and VI, wherein R is³is-OC (═ O) R⁶And R is⁶is-CH₂-O-CH₂CH₂O-CH₃、-CH₂-O-CH₂CH₂O-CH₂CH₂O-CH₃、-CH₂-O-(CH₂CH₂O)₃-CH₃、-O-CH₂CH₂O-CH₃、-O-CH₂CH₂O-CH₂CH₂O-CH₃or-O- (CH)₂CH₂O)₃-CH₃. In another embodiment, R⁶is-CH₂-O-CH₂CH₂O-CH₂CH₂O-CH₃。

In another embodiment, the compounds of the present disclosure are of any one of formulas I to VI, wherein R is⁴Is hydrogen.

In another embodiment, the compounds of the present disclosure are of any one of formulas I to VI, wherein R is⁴Is alkyl, alkenyl, alkynyl, cycloalkyl and (cycloalkyl) alkyl, any of said groups being optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of: hydroxyl, halo, haloalkyl, amino, alkylamino, dialkylamino, carboxyl, alkoxy, and alkoxycarbonyl.

In another embodiment, the compounds of the present disclosure are of any one of formulas I to VI, wherein R is⁴Is C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-6Cycloalkyl or C_3-6(cycloalkyl) (C)_1-6) Alkyl, any of said groups being optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of: hydroxy, halo (C)_1-6) Alkyl, amino, C_1-6Alkylamino radical, di (C)_1-6) Alkylamino, carboxyl, C_1-6Alkoxy andC_1-6an alkoxycarbonyl group.

In another embodiment, the compounds of the present disclosure are of any one of formulas I to VI, wherein R is⁴Is C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl or C_3-6Cycloalkyl (C)_1-4) Alkyl, any of said groups being optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of: hydroxy, halo (C)_1-4) Alkyl, amino, C_1-4Alkylamino radical, di (C)_1-4) Alkylamino, carboxyl, C_1-4Alkoxy and C_1-4An alkoxycarbonyl group.

In another embodiment, the compounds of the present disclosure are of any one of formulas I to VI, wherein R is⁴Is C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl or C_3-6Cycloalkyl (C)_1-2) Alkyl, any of said groups being optionally substituted with 1 or 2 substituents each independently selected from the group consisting of: hydroxy, halo (C) _1-2) Alkyl, amino, C_1-2Alkylamino radical, di (C)_1-2) Alkylamino, carboxyl, C_1-2Alkoxy and C_1-2Alkoxycarbonyl, and preferably optionally substituted with 1 or 2 substituents each independently selected from the group consisting of: hydroxyl, halo, trifluoromethyl, amino, methylamino, ethylamino, dimethylamino, diethylamino, carboxyl, methoxy, ethoxy, methoxycarbonyl and ethoxycarbonyl.

In another embodiment, the compounds of the present disclosure are of any one of formulas I to VI, wherein R is⁴Is unsubstituted C_1-6Alkyl, and advantageously unsubstituted C_1-4Alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, or tert-butyl). In another embodiment, R⁴Is methyl or ethyl. In another embodiment, R⁴Is methyl.

In another embodiment, the present inventionThe disclosed compounds are of any one of formulas I-VI, wherein R⁴Is C_3-6(cycloalkyl) (C)_1-4) Alkyl radicals, e.g. cyclopropyl (C)_1-4) Alkyl, cyclobutyl (C)_1-4) Alkyl, cyclopentyl (C)_1-4) Alkyl or cyclohexyl (C)_1-4) Alkyl, said group being optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of: hydroxy, halo (C) _1-4) Alkyl, amino, C_1-4Alkylamino radical, di (C)_1-4) Alkylamino, carboxyl, C_1-4Alkoxy and C_1-4Alkoxycarbonyl, and preferably optionally substituted with 1 or 2 substituents each independently selected from the group consisting of: hydroxyl, halo, trifluoromethyl, amino, methylamino, ethylamino, dimethylamino, diethylamino, carboxyl, methoxy, ethoxy, methoxycarbonyl and ethoxycarbonyl. In another embodiment, R⁴Is unsubstituted cyclopropyl (C)_1-4) An alkyl group. In another embodiment, the compounds of the present disclosure are of any one of formulas I to VI, wherein R is⁴Is unsubstituted (cyclopropyl) methyl, 2- (cyclopropyl) ethyl or 3- (cyclopropyl) propyl.

In another embodiment, the compounds of the present disclosure are of any one of formulas I to VI, wherein R is⁴Is C substituted by 1, 2 or 3 substituents_1-6Alkyl, and preferably is C_1-4Alkyl, each of said substituents being independently selected from the group consisting of: halo (e.g. fluoro) and halo (C)_1-4) Alkyl (such as, for example, trifluoro (C)_1-2) Alkyl groups).

In another embodiment, the compounds of the present disclosure are of any one of formulas I to VI, wherein R is ⁴Is C unsubstituted or substituted by 1, 2 or 3 substituents_2-6Alkenyl (e.g. C)_2-4Alkenyl), each of said substituents being independently selected from the group consisting of: halo (e.g. fluoro) and halo (C)_1-4) Alkyl (such as, for example, trifluoro (C)_1-2) Alkyl groups).

In another embodiment, the compound of the present disclosure is any one of formulas I through IIIA compound of (I), wherein R²is-C (═ O) R⁵And R is⁵Selected from the group consisting of: unsubstituted C_1-6Alkyl, unsubstituted C_7-12Alkyl, unsubstituted C_2-6Alkenyl, unsubstituted C_2-6Alkynyl, -CH₂-O-(CH₂CH₂O)_m-R⁷、-O-(CH₂CH₂O)_n-R⁷、-NH-(CH₂CH₂O)_p-R⁷Phenyl, benzyl, phenethyl, pyridyl, cycloalkyl, (cycloalkyl) alkyl, cycloalkenyl, (cycloalkenyl) alkyl, 6-membered heterocycle and (5-or 6-membered heterocycle) alkyl, wherein the phenyl, pyridyl, cycloalkyl, cycloalkenyl and heterocycle moieties are optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of: alkyl, hydroxy, halo, haloalkyl, amino, alkylamino, dialkylamino, carboxy, alkoxy, and alkoxycarbonyl; wherein the 6-membered heterocyclic ring is attached to the carbonyl carbon through a carbon atom or through a nitrogen atom; r⁷Selected from the group consisting of: hydrogen, C_1-6Alkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl, any of which groups is optionally substituted; m is an integer between 1 and 9; and n and p are each independently integers between 1 and 20. In certain embodiments, R ⁷Is hydrogen, methyl, ethyl or benzyl. In another embodiment, R⁷Is methyl.

In another embodiment, the compounds of the present disclosure are of any one of formulas I to III, wherein R is²is-C (═ O) R⁵And R is⁵Selected from the group consisting of: unsubstituted C_1-6Alkyl, unsubstituted C_7-12Alkyl, unsubstituted C_2-6Alkenyl, unsubstituted C_2-6Alkynyl, -CH₂-O-(CH₂CH₂O)_m-CH₃、-O-(CH₂CH₂O)_n-CH₃、-NH-(CH₂CH₂O)_p-CH₃Phenyl, benzyl, phenethyl, pyridyl, cycloalkyl, (cycloalkyl) alkyl, cycloalkenyl, (cycloalkenyl) alkyl, 6-membered heteroA cyclic ring and (5-or 6-membered heterocyclic) alkyl, wherein the phenyl, pyridyl, cycloalkyl, cycloalkenyl and heterocyclic moieties are optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of: alkyl, hydroxy, halo, haloalkyl, amino, alkylamino, dialkylamino, carboxy, alkoxy, and alkoxycarbonyl; 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; and wherein the 6-membered heterocyclic ring is attached to the carbonyl carbon through a carbon atom or through a nitrogen atom. In another embodiment, R⁵Selected from the group consisting of: unsubstituted C _1-6Alkyl, unsubstituted C_7-12Alkyl, unsubstituted C_2-6Alkenyl, unsubstituted C_2-6Alkynyl, -CH₂-O-(CH₂CH₂O)_m-CH₃、-O-(CH₂CH₂O)_n-CH₃、-NH-(CH₂CH₂O)_p-CH₃Phenyl, benzyl, phenethyl, pyridyl, C_3-6Cycloalkyl group, (C)_3-6Cycloalkyl) (C)_1-4) Alkyl radical, C_3-6Cycloalkenyl group, (C)_3-6Cycloalkenyl) (C)_1-4) Alkyl, 6-membered heterocycle and (5-or 6-membered heterocycle) (C)_1-4) Alkyl, wherein said phenyl, pyridyl, C_3-6Cycloalkyl radical, C_3-6The cycloalkenyl and heterocyclic moieties are optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of: c_1-4Alkyl, hydroxy, halo (C)_1-4) Alkyl, amino, (C)_1-4) Alkylamino radical, di (C)_1-4) Alkylamino, carboxyl, C_1-4Alkoxy and C_1-4Alkoxycarbonyl, and preferably optionally substituted with 1 or 2 substituents each independently selected from the group consisting of: methyl, hydroxy, halo, trifluoromethyl, amino, methylamino, ethylamino, dimethylamino, diethylamino, carboxy, methoxy, ethoxy, methoxycarbonyl and ethoxycarbonyl; m is 1, 2 or 3; n and p are each independently selected from the group consisting of: 1. 2, 3, 5 and 6; and wherein the 6-membered heterocyclic ring isTo the carbonyl carbon through a carbon atom or through a nitrogen atom.

In another embodiment, the compounds of the present disclosure are of any one of formulas I to III, wherein R is²is-C (═ O) R⁵And R is⁵Is unsubstituted C_1-6Alkyl, unsubstituted C_2-6Alkenyl or C_2-6Alkynyl. In another embodiment, R⁵Is unsubstituted C_1-4An alkyl group. In another embodiment, R⁵Is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl or sec-butyl. In another embodiment, R⁵Is unsubstituted C_1-4An alkyl group. In another embodiment, R⁵Is methyl. In another embodiment, R⁵Is ethyl, propyl or n-butyl.

In another embodiment, the compounds of the present disclosure are of any one of formulas I to III, wherein R is²is-C (═ O) R⁵And R is⁵Is unsubstituted C_7-12An alkyl group. In another embodiment, R⁵Is heptyl, octyl, nonyl, decyl, undecyl or dodecyl. In another embodiment, R⁵Is an undecyl group.

In another embodiment, the compounds of the present disclosure are of any one of formulas I to III, wherein R is²is-C (═ O) R⁵And R is⁵is-CH₂-O-CH₂CH₂O-CH₃、-CH₂-O-CH₂CH₂O-CH₂CH₂O-CH₃、-CH₂-O-(CH₂CH₂O)₃-CH₃、-O-CH₂CH₂O-CH₃、-O-CH₂CH₂O-CH₂CH₂O-CH₃or-O- (CH)₂CH₂O)₃-CH₃. In another embodiment, R⁵is-CH₂-O-CH₂CH₂O-CH₂CH₂O-CH₃。

In another embodiment, the compounds of the present disclosure are of formula IV Compound (I) wherein R⁵Selected from the group consisting of: unsubstituted C_1-6Alkyl, unsubstituted C_7-12Alkyl, unsubstituted C_2-6Alkenyl, unsubstituted C_2-6Alkynyl, -CH₂-O-(CH₂CH₂O)_m-R⁷、-O-(CH₂CH₂O)_n-R⁷、-NH-(CH₂CH₂O)_p-R⁷Phenyl, benzyl, phenethyl, pyridyl, cycloalkyl, (cycloalkyl) alkyl, cycloalkenyl, (cycloalkenyl) alkyl, 6-membered heterocycle and (5-or 6-membered heterocycle) alkyl, wherein the phenyl, pyridyl, cycloalkyl, cycloalkenyl and heterocycle moieties are optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of: alkyl, hydroxy, halo, haloalkyl, amino, alkylamino, dialkylamino, carboxy, alkoxy, and alkoxycarbonyl; wherein the 6-membered heterocyclic ring is attached to the carbonyl carbon through a carbon atom or through a nitrogen atom; r⁷Selected from the group consisting of: hydrogen, C_1-6Alkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl, any of which groups is optionally substituted; m is an integer between 1 and 9; and n and p are each independently integers between 1 and 20. In certain embodiments, R⁷Is hydrogen, methyl, ethyl or benzyl. In another embodiment, R⁷Is methyl.

In another embodiment, the compounds of the present disclosure are of formula IV wherein R is ⁵Selected from the group consisting of: unsubstituted C_1-6Alkyl, unsubstituted C_7-12Alkyl, unsubstituted C_2-6Alkenyl, unsubstituted C_2-6Alkynyl, -CH₂-O-(CH₂CH₂O)_m-CH₃、-O-(CH₂CH₂O)_n-CH₃、-NH-(CH₂CH₂O)_p-CH₃Phenyl, benzyl, phenethyl, pyridyl, cycloalkyl, (cycloalkyl) alkyl, cycloalkenyl, (cycloalkenyl) alkyl, 6-membered heterocycle and (5-or 6-membered heterocycle) alkyl, wherein the phenyl, pyridyl, cycloalkyl, cycloalkenyl and heterocycle moieties are optionally substituted with 1, 2 or3 substituents each independently selected from the group consisting of: alkyl, hydroxy, halo, haloalkyl, amino, alkylamino, dialkylamino, carboxy, alkoxy, and alkoxycarbonyl; 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; and wherein the 6-membered heterocyclic ring is attached to the carbonyl carbon through a carbon atom or through a nitrogen atom. In another embodiment, R⁵Selected from the group consisting of: unsubstituted C₁-₆Alkyl, unsubstituted C_7-12Alkyl, unsubstituted C_2-6Alkenyl, unsubstituted C_2-6Alkynyl, -CH₂-O-(CH₂CH₂O)_m-CH₃、-O-(CH₂CH₂O)_n-CH₃、-NH-(CH₂CH₂O)_p-CH₃Phenyl, benzyl, phenethyl, pyridyl, C_3-6Cycloalkyl group, (C)_3-6Cycloalkyl) (C)_1-4) Alkyl radical, C_3-6Cycloalkenyl group, (C) _3-6Cycloalkenyl) (C)_1-4) Alkyl, 6-membered heterocycle and (5-or 6-membered heterocycle) (C)_1-4) Alkyl, wherein said phenyl, pyridyl, C_3-6Cycloalkyl radical, C_3-6The cycloalkenyl and heterocyclic moieties are optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of: c_1-4Alkyl, hydroxy, halo (C)_1-4) Alkyl, amino, (C)_1-4) Alkylamino radical, di (C)_1-4) Alkylamino, carboxyl, C_1-4Alkoxy and C_1-4Alkoxycarbonyl, and preferably optionally substituted with 1 or 2 substituents each independently selected from the group consisting of: methyl, hydroxy, halo, trifluoromethyl, amino, methylamino, ethylamino, dimethylamino, diethylamino, carboxy, methoxy, ethoxy, methoxycarbonyl and ethoxycarbonyl; m is 1, 2 or 3; n and p are each independently selected from the group consisting of: 1. 2, 3, 5 and 6; and wherein the 6-membered heterocyclic ring is attached to the carbonyl carbon through a carbon atom or through a nitrogen atom.

In another embodimentThe compounds of the present disclosure are of formula IV, wherein R⁵Is unsubstituted C_1-6Alkyl, unsubstituted C_2-6Alkenyl or C_2-6Alkynyl. In another embodiment, R ⁵Is unsubstituted C_1-4An alkyl group. In another embodiment, R⁵Is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl or sec-butyl. In another embodiment, R⁵Is unsubstituted C_1-4An alkyl group. In another embodiment, R⁵Is methyl. In another embodiment, R⁵Is ethyl, propyl or n-butyl.

In another embodiment, the compounds of the present disclosure are of formula IV wherein R is⁵Is unsubstituted C_7-12An alkyl group. In another embodiment, R⁵Is heptyl, octyl, nonyl, decyl, undecyl or dodecyl. In another embodiment, R⁵Is an undecyl group.

In another embodiment, the compounds of the present disclosure are of formula IV wherein R is⁵is-CH₂-O-CH₂CH₂O-CH₃、-CH₂-O-CH₂CH₂O-CH₂CH₂O-CH₃、-CH₂-O-(CH₂CH₂O)₃-CH₃、-O-CH₂CH₂O-CH₃、-O-CH₂CH₂O-CH₂CH₂O-CH₃or-O- (CH)₂CH₂O)₃-CH₃. In another embodiment, R⁵is-CH₂-O-CH₂CH₂O-CH₂CH₂O-CH₃。

In another embodiment, the compounds of the present disclosure are of any one of formulas I to III, wherein R is²is-C (═ O) R⁵，R³is-OC (═ O) R⁶And R is⁵And R⁶Are identical, i.e. are compounds of the formula V, in which R is⁵As defined above, with the proviso that the compound is not

In another embodiment, in the compounds of formula V, each R is ⁵Is butyl or undecyl. In another embodiment, each R is⁵is-CH₂-O-CH₂CH₂O-CH₂CH₂O-CH₃。

In another embodiment, the compounds of the present disclosure are of any one of formulas I to III, wherein R is³is-OC (═ O) R⁶And R is⁵And R⁶Different.

In another embodiment, the compound of the present disclosure is a compound of formula II or formula III, wherein

R¹Is H or unsubstituted C_1-6An alkyl group;

R²is-C (O) (C)_1-6) An alkyl group;

R³is H or OH; and is

R⁴Is unsubstituted C_1-6An alkyl group, a carboxyl group,

with the proviso that said compound is not

In another embodiment, the compounds of the present disclosure are compounds of formula II or formula III, which are oxycodone enol esters and pharmaceutically acceptable salts and solvates thereof, wherein R is₁Is methyl, R³Is OH, R⁴Is methyl, and R²is-C (═ O) R⁵Wherein R is⁵As defined above for formula II. In another embodiment, the compounds of the present disclosure are compounds of formula II or formula III, respectively, having the structures

And pharmaceutically acceptable salts and solvates thereof. Alternatively, these oxycodone enol esters and pharmaceutically acceptable salts and solutions thereofThe compound is a compound of formula IV wherein R₁Is methyl, R³¹Is OH, R⁴Is methyl, and R²is-C (═ O) R⁵Wherein R is ⁵As defined above for II.

In another embodiment, the compounds of the present disclosure are compounds of formula II or formula III, which are oxymorphone enol esters and pharmaceutically acceptable salts and solvates thereof, wherein R is₁Is hydrogen, R³Is OH, R⁴Is methyl, and R²is-C (═ O) R⁵Wherein R is⁵As defined above for formula II. Alternatively, these oxymorphone enol esters and pharmaceutically acceptable salts and solvates thereof are compounds of formula IV, wherein R is₁Is hydrogen, R³¹Is OH, R⁴Is methyl, and R⁵As defined above for formula II.

In another embodiment, the compounds of the present disclosure are of any one of formulas II to IV, which are hydrocodone enol esters and pharmaceutically acceptable salts and solvates thereof, wherein R is₁Is methyl, R³/R³¹Is H, R⁴Is methyl, R²is-C (═ O) R⁵And R is⁵As defined above for formula II, with the proviso that the compound is not

In another embodiment, the compounds of the present disclosure are of any one of formulas II through IV, which are hydromorphone enol esters and pharmaceutically acceptable salts and solvates thereof, wherein R is₁Is hydrogen, R³/R³¹Is H, R⁴Is methyl, and R²is-C (═ O) R⁵And R is⁵As defined above for formula II, with the proviso that the compound is not

In another embodiment, the compounds of the present disclosure include:

and pharmaceutically acceptable salts and solvates thereof.

In another embodiment, the compounds of the present disclosure include:

and pharmaceutically acceptable salts and solvates thereof.

Optional substituents attached to the aryl, phenyl, and heteroaryl rings each replace a hydrogen atom that would otherwise be present at any position on the aryl, phenyl, or heteroaryl ring.

Useful halo or halogen groups include fluoro, chloro, bromo, and iodo.

Useful alkyl groups are selected from straight and branched C_1-12An alkyl group. Typical C_1-12Alkyl includes methyl (Me), ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, dodecyl, isopropyl, sec-butyl, tert-butyl, isobutyl, isopentyl, neopentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 3-ethylbutyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-dimethylbutyl, 2, 3-dimethylbutyl, 3, 3-dimethylbutyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 1, 2-dimethylpentyl, 1, 3-dimethylpentyl, 1, 2-dimethylhexyl, 1, 3-dimethylhexyl, 3-dimethylhexyl, 1, 2-dimethylheptyl, 1, 3-dimethylheptyl, and 3, 3-dimethylheptyl, and the like. In one embodiment, useful C_1-12Alkyl being straight-chain C_1-12An alkyl group. In another embodiment, useful alkyl groups are selected from straight and branched chain C_1-10Alkyl, i.e. straight-chain C_1-10Alkyl and branched C_3-10An alkyl group. In another embodiment, useful alkyl groups are selected from straight and branched chain C_1-6Alkyl, i.e. straight-chain C_1-6Alkyl and branched C_3-6An alkyl group. Typical C_1-6Alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, isobutyl, pentyl, 3-pentyl, hexyl and the like. In one embodiment, useful alkyl groups are selected from straight and branched chain C_1-4Alkyl, i.e. straight-chain C_1-4Alkyl and branched C_3-4An alkyl group. Typical C_1-4Alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl and isobutyl. Typical C_1-2Alkyl groups include methyl and ethyl. In this application, C_1-6Alkyl means straight and branched C _1-6Alkyl radical, and C_1-4Alkyl means straight and branched C_1-4Alkyl, as defined above in this paragraph. In another embodiment, useful alkyl groups are selected from straight and branched chain C_7-12An alkyl group.

Useful alkenyl groups are selected from straight and branched C_2-12An alkenyl group. As used herein, the term "C_2-12Alkenyl "by itself or when used as part of another group refers to straight and branched chain acyclic hydrocarbons having from 2 to 12 carbon atoms and including at least one carbon-carbon double bond. Representative typical C_2-12Alkenyl groups include vinyl (vinyl), allyl, 1-butenyl, 2-butenyl, isobutenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl, 2-methyl-2-butenyl, 2, 3-dimethyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, and the like. In one embodimentAvailable C_2-12Alkenyl is C_2-10An alkenyl group. In another embodiment, useful C_2-12Alkenyl is C_2-6An alkenyl group. Typical C_2-6Alkenyl groups include vinyl (ethenyl) (i.e., vinyl (vinvl)), allyl, 1-butenyl, 2-butenyl, isobutenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl, 2-methyl-2-butenyl, 2, 3-dimethyl-2-butenyl, 1-hexenyl, 2-hexenyl, and 3-hexenyl. Typical C _2-4Alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, and sec-butenyl.

Useful alkynyl groups are selected from straight and branched C_2-12Alkynyl. As used herein, the term "C_2-12Alkynyl "by itself or when used as part of another group refers to straight and branched chain acyclic hydrocarbons having from 2 to 12 carbon atoms and including at least one carbon-carbon triple bond. Representative straight and branched chains C_2-12Alkynyl includes ethynyl (alkynyl), propynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, pentyn-2-yl, 3-methylbutyn-1-yl, pentyn-4-yl, hexyn-1-yl, hexyn-2-yl, hexyn-3-yl and the like. In one embodiment, C_2-12Alkynyl is C_2-10Alkynyl. In another embodiment, C_2-12Alkynyl is C_2-6Alkynyl. Typical C_2-6Alkynyl groups include ethynyl (i.e., ethynyl), propynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, pentyn-2-yl, 3-methylbutyn-1-yl, pentyn-4-yl, and hexyn-1-yl. In another embodiment, C_2-10Alkynyl is C_2-4Alkynyl. Typical C_2-4Alkynyl includes ethynyl, propynyl, butyn-1-yl and butyn-2-yl.

Useful haloalkyl groups include the above-mentioned C substituted with one or more fluorine, chlorine, bromine or iodine atoms _1-12Any of the alkyl groups, preferably C as mentioned above_1-6Any of the alkyl groups, and preferably C as mentioned above_1-4Any of the alkyl groups (e.g., fluoromethyl, difluoromethyl, difluorochloromethyl, trifluoromethyl, pentafluoroethyl, 1-difluoroethyl, 2, 2, 2-trifluoroethyl3, 3, 3-trifluoropropyl, 4, 4, 4-trifluorobutyl, and trichloromethyl).

Useful cycloalkyl groups are selected from those having 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms (i.e., C) containing 1, 2, or 3 rings_3-12Cycloalkyl) or a saturated cyclic hydrocarbon group of a specified carbon number. In one embodiment, the cycloalkyl group has one or two rings. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalin, and adamantyl. In another embodiment, cycloalkyl is C_3-6A cycloalkyl group. Typical C_3-6Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Useful cycloalkenyl groups are selected from those containing 1, 2 or 3 rings having 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms (i.e., C)_4-C₁₂Cycloalkenyl) or partially unsaturated (i.e., containing one or two double bonds) cyclic hydrocarbon groups of the specified carbon number. In one embodiment, cycloalkenyl has one or two rings. In another embodiment, cycloalkenyl is C _3-8A cycloalkenyl group. In another embodiment, cycloalkenyl is C_3-7A cycloalkenyl group. In another embodiment, cycloalkenyl is C_3-6A cycloalkenyl group. In one embodiment, cycloalkenyl groups contain one double bond. Exemplary cycloalkenyl groups containing one double bond include cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, and cyclodecenyl. In another embodiment, cycloalkenyl groups contain two double bonds. Preferably, cycloalkenyl groups containing two double bonds have 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms (i.e., C)_5-C₁₂A cycloalkadienyl group). Exemplary cycloalkenyl groups having two double bonds include cyclopentadienyl, cyclohexadienyl, cycloheptadienyl, cyclooctadienyl, cyclononadienyl, and cyclodecadienyl.

Useful alkoxy groups include C as mentioned above_1-12Oxygen substituted with any one of alkyl (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, t-butoxy, t-butyloxy, n-butyloxy,nonanoxy, decyloxy, undecyloxy and dodecyloxy), preferably by C_1-6Any of the alkyl groups, and more preferably by C _1-4Any of the alkyl groups is substituted.

Useful halo (C)_1-6) Alkoxy includes halo (C) as mentioned above_1-6) Oxygen substituted with any one of the alkyl groups (e.g., fluoromethoxy, difluoromethoxy, trifluoromethoxy, and 2, 2, 2-trifluoroethoxy).

Useful (cycloalkyl) alkyl groups include the above-mentioned C substituted with any of the above-mentioned cycloalkyl groups_1-12Any of the alkyl groups, and preferably C as mentioned above_1-6Any of the alkyl groups (e.g., (cyclopropyl) methyl, 2- (cyclopropyl) ethyl, (cyclopropyl) propyl, (cyclobutyl) methyl, (cyclopentyl) methyl, and (cyclohexyl) methyl).

Useful (cycloalkenyl) alkyl groups include the C mentioned above substituted with any of the cycloalkenyl groups mentioned above_1-12Any of the alkyl groups, and preferably C as mentioned above_1-6Any of the alkyl groups (e.g., (cyclobutenyl) methyl, 2- (cyclobutenyl) ethyl, (cyclobutenyl) propyl, (cyclopentenyl) methyl, (cyclohexenyl) methyl, and (cyclopentadienyl) methyl).

Aryl radicals which may be used are C_6-14Aryl radicals, especially C_6-10And (4) an aryl group. Typical C_6-14Aryl includes phenyl (Ph), naphthyl, phenanthryl, anthracyl, indenyl, azulenyl, biphenyl, biphenylene and fluorenyl, more preferably phenyl, naphthyl and biphenyl.

Useful arylalkyl groups include the above-mentioned C substituted with any of the above-mentioned aryl groups_1-12Any of the alkyl groups, and preferably C as mentioned above_1-6Any of the alkyl groups (e.g., benzyl and phenethyl).

Useful arylalkenyl groups include the above-mentioned C substituted with any of the above-mentioned aryl groups_2-6Any of the alkenyl groups (e.g., styryl).

Useful arylalkynyl groups include the aryl groups mentioned aboveC mentioned above substituted by any one of the radicals_2-6Any of the alkynyl groups (e.g., phenylethynyl).

Useful aryloxy groups include oxygen substituted with any of the aryl groups mentioned above (e.g., phenoxy).

Useful aralkoxy or arylalkoxy groups include oxygen substituted with any of the arylalkyl groups mentioned above (e.g., benzyloxy).

Useful (arylalkoxy) carbonyl groups include carbonyl groups substituted with any of the arylalkoxy groups mentioned above (e.g., (benzyloxy) carbonyl).

The terms "heterocycle" and "heterocyclyl" are used herein to mean a saturated or partially unsaturated 3-7 membered monocyclic or 7-10 membered bicyclic ring system consisting of carbon atoms and one to four heteroatoms independently selected from the group consisting of O, N and S, wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, the nitrogen may optionally be quaternized, and includes any bicyclic group in which any of the above-defined heterocycles are fused to a benzene ring, and wherein the heterocycle may be substituted on a carbon atom or a nitrogen atom if the resulting compound is stable. In one embodiment, the 3 to 7 membered monocyclic heterocycle is a saturated or unsaturated non-aromatic ring. A 3-membered heterocyclic ring contains 1 heteroatom, a 4-membered heterocyclic ring can contain up to 2 heteroatoms, a 5-membered heterocyclic ring can contain up to 4 heteroatoms, a 6-membered heterocyclic ring can contain up to 4 heteroatoms, and a 7-membered heterocyclic ring can contain up to 5 heteroatoms. Each heteroatom is independently selected from: nitrogen, which may be quaternized; oxygen; and sulfur, including sulfoxides and sulfones. The 3-to 7-membered heterocyclic ring may be attached through a nitrogen or carbon atom. The 7-to 10-membered bicyclic heterocycle contains 1 to 4 heteroatoms independently selected from: nitrogen, which may be quaternized; oxygen; and sulfur, including sulfoxides and sulfones. The 7-to 10-membered bicyclic heterocycle may be attached through a nitrogen or carbon atom. Examples of heterocycles include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, imidazolinyl, pyrazolidinyl, tetrahydrofuranyl, oxazolidinyl, 2-oxaoxazolidinyl, tetrahydrothienyl, imidazolinyl, hexahydropyrimidyl, and benzodiazepine In one embodiment, the heterocycle is a 5 or 6 membered heterocycle. Typical 5-membered heterocyclic groups include pyrrolidinyl, imidazolinyl, tetrahydrofuranyl, oxazolidinyl, 2-oxaoxazolidinyl, tetrahydrothienyl, and imidazolidinyl. Typical 6-membered heterocyclic groups include piperidinyl, piperazinyl, morpholinyl, pyrazolidinyl, and hexahydropyrimidyl.

Useful (heterocyclyl) alkyl or (heterocyclo) alkyl groups include the above-mentioned C substituted with any of the above-mentioned heterocyclyl or heterocyclic groups_1-10Any of the alkyl groups, and preferably C as mentioned above_1-6Any of the alkyl groups (e.g., (pyrrolidin-2-yl) methyl, (pyrrolidin-1-yl) methyl, (piperidin-1-yl) methyl, (morpholin-4-yl) methyl, (2-oxooxazolidin-4-yl) methyl, 2- (2-oxooxazolidin-4-yl) ethyl, (2-oxoimidazolin-1-yl) methyl, (2-oxoimidazolin-1-yl) ethyl, and (2-oxoimidazolin-1-yl) propyl).

As used herein, the term "heteroaryl" refers to a group having 5 to 14 ring atoms, sharing 6, 10, or 14 pi electrons in a cyclic array and containing a carbon atom and 1, 2, or 3 oxygen, nitrogen, or sulfur heteroatoms or 4 nitrogen atoms. In one embodiment, the heteroaryl is a 5 to 10 membered heteroaryl. In one embodiment, heteroaryl is a 5 or 6 membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from O, N and S. Examples of heteroaryl groups include thienyl, furyl, pyranyl, 2H-pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, isoindolyl, 3H-indolyl, indazolyl, purinyl, isoquinolyl, quinolinyl, pyrimidinyl, thiazolyl, isothiazolyl, and isoxazolyl. The 5-membered heteroaryl group can contain up to 4 heteroatoms. The 6-membered heteroaryl group can contain up to 3 heteroatoms.

As used herein, the term "amino" or "amino group" refers to-NH₂。

Useful aminoalkyl groups include C as mentioned above substituted with one or more amino groups_1-112Any of the alkyl groups, and preferably C as mentioned above_1-6Any one of alkyl, and morePreferably C as mentioned above_1-4Any one of alkyl groups.

Useful alkylamino and dialkylamino groups are-NHR respectively¹³and-NR¹³R¹⁴Wherein R is¹³And R¹⁴Each independently selected from C_1-10Alkyl, preferably C_1-6Alkyl, and more preferably C_1-4An alkyl group.

As used herein, the term "aminocarbonyl" refers to-C (═ O) NH₂。

Useful alkylcarbonyl groups include C as mentioned above_1-10Carbonyl substituted by any one of the alkyl groups, i.e., -C (═ O) -.

Useful arylcarbonyl groups include carbonyl groups substituted with any of the aryl groups mentioned above (e.g., benzoyl).

Useful alkylcarbonyloxy or acyloxy groups include oxygen substituted with any of the alkylcarbonyl groups mentioned above.

Useful alkylcarbonylamino or amido groups include any of the above-mentioned alkylcarbonyl groups attached to the amino nitrogen, such as methylcarbonylamino.

The term "carboxamide group" as used herein refers to the formula-C (═ O) NR ¹⁵R¹⁶Wherein R is¹⁵And R¹⁶Each independently hydrogen, optionally substituted C_1-10Alkyl or optionally substituted aryl. Exemplary carboxamide groups include-CONH₂、-CON(H)CH₃、-CON(CH₃)₂and-CON (H) Ph.

As used herein, the term "sulfonamide" refers to compounds of the formula-SO₂NR¹⁷R¹⁸Wherein R is¹⁷And R¹⁸Each independently hydrogen, optionally substituted C_1-10Alkyl or optionally substituted aryl. Exemplary sulfonamide groups include-SO₂NH₂、-SO₂N(H)CH₃and-SO₂N(H)Ph。

As used herein, the term "thiol" refers to-SH.

Useful mercaptoalkyl radicals include the C mentioned above substituted by-SH groups_1-12Any of the alkyl groups, and preferably C as mentioned above_1-6Any one of alkyl groups.

As used herein, the term "carboxy" refers to-COOH.

Useful carboxyalkyl groups include the C mentioned above substituted by-COOH_1-12Any of the alkyl groups, and preferably C as mentioned above_1-6Any one of alkyl groups.

As used herein, the term "hydroxy" refers to — OH.

Useful hydroxyalkyl groups include the above-mentioned C groups substituted with one or more hydroxy groups_1-12Any of the alkyl groups, preferably C as mentioned above_1-6Any of the alkyl groups, and preferably C as mentioned above_1-4Any one of alkyl groups. Representative hydroxy group (C) _1-6) Alkyl groups include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1, 2-dihydroxyethyl, 2-hydroxypropyl, 3-hydroxybutyl, 4-hydroxybutyl, 2-hydroxy-1-methylpropyl and 1, 3-dihydroxypropan-2-yl.

As used herein, the term "cyano" refers to — CN.

As used herein, the term "nitro" refers to-NO₂。

As used herein, the term "ureido" refers to-NH-C (═ O) -NH₂。

As used herein, the term "azido" refers to-N₃。

As used herein, the term "ambient temperature" means the ambient temperature. The ambient temperature in the room is the same as room temperature, from about 20 ℃ to about 25 ℃.

As used herein, the term "about" used in conjunction with a measured quantity refers to the normal variation in the measured quantity as would be expected by one skilled in the art of making measurements and exercising a level of care commensurate with the accuracy of the measurement target and the measurement equipment. Typically, the term "about" includes the recited value ± 10%. Thus, "about 10" means 9 to 11. The term "optionally substituted" as used herein refers to a group that may be unsubstituted or substituted.

When not otherwiseWhen indicated, the optional substituents on the optionally substituted group include one or more groups, typically 1, 2 or 3 groups, independently selected from the group consisting of: halo, halo (C) as mentioned hereinbefore _1-6) Alkyl, aryl, heterocyclic, cycloalkyl, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, aryl (C)_1-6) Alkyl, aryl (C)_2-6) Alkenyl, aryl (C)_2-6) Alkynyl, cycloalkyl (C)_1-6) Alkyl, heterocycle (C)_1-6) Alkyl, hydroxy (C)_1-6) Alkyl, amino (C)_1-6) Carboxyl group (C)_1-6) Alkyl, alkoxy (C)_1-6) Alkyl, nitro, amino, ureido, cyano, alkylcarbonylamino, hydroxy, thiol, alkylcarbonyloxy, aryloxy, ar (C)_1-6) Alkoxy, carboxamide, sulfonamide, azido, C_1-6Alkoxy, halo (C)_1-6) Alkoxy, carboxyl, aminocarbonyl, (═ O) and mercapto (C)_1-6) An alkyl group. Preferred optional substituents include halo, halo (C)_1-6) Alkyl, hydroxy (C)_1-6) Alkyl, amino (C)_1-6) Alkyl, hydroxy, nitro, C_1-6Alkyl radical, C_1-6Alkoxy, halo (C)_1-6) Alkoxy and amino.

The compounds of the present disclosure encompass all salts of the compounds of any one of formulae I-VI. The present invention preferably includes all non-toxic pharmaceutically acceptable salts of the compounds of the present disclosure. Examples of pharmaceutically acceptable addition salts include inorganic and organic acid addition salts and basic salts. Pharmaceutically acceptable salts include, but are not limited to, metal salts, such as sodium, potassium, cesium and the like; alkaline earth metals such as calcium salts, magnesium salts, and the like; organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N' -dibenzylethylenediamine salt and the like; inorganic acid salts such as hydrochloride, hydrobromide, phosphate, sulfate, etc.; organic acid salts such as citrate, lactate, tartrate, maleate, fumarate, mandelate, acetate, dichloroacetate, trifluoroacetate, oxalate, formate and the like; sulfonates such as methanesulfonate, benzenesulfonate, p-toluenesulfonate and the like; and amino acid salts such as arginine salts, asparagine salts, glutamic acid salts, and the like.

Acid addition salts may be formed by mixing a solution of a particular compound of the present invention with a solution of a pharmaceutically acceptable non-toxic acid such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid, dichloroacetic acid, and the like. Basic salts may be formed by mixing a solution of a compound of the invention with a solution of a pharmaceutically acceptable non-toxic base such as sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, and the like.

The compounds of the present disclosure also encompass solvates of any of the compounds of formulas I-VI. Solvates do not generally significantly alter the physiological activity or toxicity of the compound and are therefore useful as pharmacological equivalents. As used herein, the term "solvate" is a combination, physical association, and/or solvation of a compound of the present invention with a solvent molecule, such as, for example, a di-, mono-, or semi-solvate, wherein the ratio of solvent molecules to a compound of the present invention is about 2: 1, about 1: 1, or about 1: 2, respectively. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, solvates may be isolated, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. Thus, "solvate" encompasses both solution phase and isolatable solvates. The compounds of the present disclosure may exist as solvates with pharmaceutically acceptable solvents (e.g., water, methanol, ethanol, etc.), and it is intended that the present invention include both solvate and non-solvate forms of the compounds of any one of formulas I-VI. One type of solvate is a hydrate. "hydrates" refers to a particular subgroup of solvates, wherein the solvent molecule is water. Solvates are generally useful as pharmacological equivalents. The preparation of solvates is known in the art. See, e.g., m.caira et al, j.pharmaceut.sci., 93 (3): 601-611(2004), which describes the preparation of solvates of fluconazole with ethyl acetate and water. Van binder et al, AAPS pharm. sci. tech., 5 (1): article12(2004) and a.l.bingham et al, chem.commun.: 603-604(2001) describe the analogous preparation of solvates, hemisolvates, hydrates, etc. A typical, non-limiting method of preparing the solvate will comprise dissolving a compound of any one of formulae I-VI in the desired solvent (organic, water, or mixtures thereof) at a temperature of from above about 20 ℃ to about 25 ℃, followed by cooling the solution at a rate sufficient to form crystals, and isolating the crystals by known methods, such as filtration. Analytical techniques such as infrared spectroscopy can be used to confirm the presence of solvent in the solvate crystals.

The compounds of the present disclosure may be isotopically labeled (i.e., radiolabeled). Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as²H、³H、¹¹C、¹³C、¹⁴C、¹⁵N、¹⁸O、¹⁷O、³¹P、³²P、³⁵S、¹⁸F and³⁶cl, and is preferably³H、¹¹C and¹⁴C. in view of this disclosure, isotopically labeled compounds of the present invention can be prepared by methods known in the art. For example, tritiated compounds of the present disclosure can be prepared by introducing tritium into a particular compound by catalytic dehalogenation of tritium. The method may comprise reacting a suitable halogen-substituted precursor of a compound of the present disclosure with tritium gas in the presence of a suitable catalyst, such as Pd/C, in the presence of a base. Other suitable methods for preparing tritiated Compounds can be found in Filer, Isotips in the Physical and biological Sciences, Vol.1, laboratory Compounds (part A), Chapter 6 (1987). Can be obtained by adopting a container with¹⁴C carbon starting material preparation¹⁴C carbon labeled compound.

Isotopically labeled compounds of the present disclosure, and pharmaceutically acceptable salts and solvates thereof, are useful as radioligands to test the binding of the compounds to opioid receptors. For example, radiolabeled compounds of the present disclosure may be used to characterize specific binding of a test or candidate compound to a receptor. Binding assays utilizing such radiolabeled compounds may provide an in vitro alternative to animal tests for assessing chemical structure-activity relationships. For example, receptor assays can be performed in a competition assay with a fixed concentration of a radiolabeled compound of the disclosure and an increasing concentration of a test compound. In one non-limiting embodiment, the present invention provides a method for screening a candidate compound for the ability to bind to an opioid receptor, the method comprising: a) introducing a fixed concentration of a radiolabeled compound of the present disclosure into a receptor under conditions that allow the radiolabeled compound to bind to the receptor to form a complex; b) titrating the complex with a candidate compound; and c) determining the binding of said candidate compound to said receptor.

Some of the compounds disclosed herein may contain one or more asymmetric centers and thus may give rise to enantiomers, diastereomers, and other stereoisomeric forms, such as epimers. The present invention is intended to cover all such possible forms, as well as their racemic and resolved forms and the use of mixtures thereof. In view of this disclosure, the individual enantiomers may be separated according to methods known to those of ordinary skill in the art. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, they are intended to include both E and Z geometric isomers unless otherwise indicated. All tautomers are also intended to be encompassed by the present invention.

As used herein, the term "stereoisomer" is a general term for all isomers of individual molecules that differ only in the orientation of their atoms in space. It includes enantiomers and isomers of compounds having more than one chiral center that are not mirror images of each other (diastereomers).

The term "chiral center" refers to a carbon atom to which four different groups are attached.

The term "epimer" refers to a diastereomer having an opposite configuration in only one of two or more tetrahedral stereocenters present in the corresponding molecular entity.

The term "stereocenter" is a group with atoms such that the interchange of any two groups results in a stereoisomer.

The term "enantiomer" or "enantiomer" refers to a molecule that is non-superimposable on mirror image and thus optically active, wherein the enantiomer rotates the plane of polarized light in one direction and its mirror image compound rotates the plane of polarized light in the opposite direction.

The term "racemic" refers to a mixture of equal parts of enantiomers and which mixture is not optically active.

The term "resolution" refers to the separation or concentration or depletion of one of the two enantiomeric forms of a molecule.

The terms "a" or "an" mean one or more than one.

The term "treating" refers to administering a therapy to a statistically significant extent or to an extent detectable by one of skill in the art in an amount, manner, or mode effective to ameliorate a condition, symptom, or parameter associated with a disorder or prevent progression of a disorder. The effective amount, manner, or mode may vary from subject to subject, and may be tailored to the patient.

Open-ended terms such as "comprising," including, "" containing, "and" containing "mean" including.

The term "effective amount" or "therapeutically effective amount" of a compound of the present disclosure refers to an amount of a compound of the present disclosure that is capable of delivering a therapeutically effective dose of the parent opioid when administered as indicated.

Suitable hydroxy-protecting Groups for PG are well known and include, for example, any suitable hydroxy-protecting group disclosed in Wuts, p.g.m and Greene, t.w., Greene's Protective Groups in Organic Synthesis, 4 th edition, pages 16-430 (j.wiley & Sons, 2007), which is incorporated herein by reference in its entirety. As used herein, the term "hydroxyl protecting group" refers to a group that blocks (i.e., protects) the hydroxyl functionality when reacted on other functional groups or a portion of a molecule. The skilled artisan will be familiar with the selection, attachment and cleavage of protecting groups, and will understand that many different protecting groups are known in the art, the suitability of one or the other depending on the particular synthetic scheme planned. Suitable hydroxyl protecting groups can generally be selectively introduced and removed using mild reaction conditions that do not interfere with other moieties of the subject compounds. These protecting groups may be introduced or removed at a convenient stage using methods known in the art. The chemistry of such groups, methods of their introduction and removal are known in the art and can be found, for example, in Greene, t.w. and Wuts, p.g.m. above. Additional hydroxyl protecting groups can be found, for example, in U.S. patent No. 5,952,495, U.S. patent application publication nos. 2008/0312411, WO 2006/035195, and WO 98/02033, which are incorporated by reference herein in their entirety. Suitable hydroxy protecting groups include methoxymethyl, tetrahydropyranyl, t-butyl, allyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, acetyl, pivaloyl, benzoyl, benzyl (Bn), and p-methoxybenzyl.

As used herein, the term "delayed onset" or "delayed onset" refers to an increase in the onset time of a post-administration therapeutic effect provided by certain compounds of the present disclosure when acting as prodrugs compared to a corresponding amount of the parent compound (e.g., the expected biologically active moiety) over the same length of time via the same route of administration.

As used herein, the terms "reduced abuse potential", and the like, refer to the reduced potential of certain compounds of the present disclosure for inappropriate non-medical and/or recreational administration, as compared to the parent compound, wherein, however, the compounds are still capable of delivering the desired therapeutic effect when administered as indicated.

Terms used with respect to abuse potential or overdose potential, such as "reduced", "attenuated", or "reduced", refer to at least about a 10% reduction in abuse potential or overdose potential as measured by one or more standard measures of such abuse potential or overdose as known in the art, with greater percentage variation being preferred for reduction in abuse potential and overdose potential. For example, the reduction may be greater than 25%, 35%, 45%, 55%, 65%, 75%, 85%, 95%, 96%, 97%, 98%, or 99%.

As used herein, the term "opioid" refers to a compound that binds to opioid receptors, particularly to the μ (mu), κ (kappa), (delta), and ORL1 receptors. Opioid compounds for use herein include opioid agonists, opioid partial agonists, and opioid antagonists, such as oxycodone, hydromorphone, oxymorphone, buprenorphine, and hydrocodone. In one embodiment, the opioid compound (or parent compound) for use herein is oxycodone or hydrocodone. In another embodiment, the opioid compound (or parent compound) is oxycodone.

As used herein, a compound that binds to a receptor and mimics the modulation of an endogenous ligand is defined as an "agonist". Compounds that bind to receptors and are only partially effective as agonists are defined as "partial agonists". Compounds that bind to the receptor but do not produce a modulating effect, but block the binding of the ligand to the receptor, are defined as "antagonists". (Ross and Kenakin, "Chapter 2: pharmaceuticals: Mechanisms of Drug Action and the correlation Between Drug contributions and effects", pages 31-32, Goodman & Gilman's the pharmaceutical Basis of Therapeutics, 10 th edition (J.G.Hardman, L.E.Limbird and A.Goodman-Gilman eds., 2001)).

As used herein, the term "opioid therapy" refers to the administration of an opioid to a subject to treat or prevent a condition for which an opioid compound has been demonstrated to be effective.

In certain embodiments, opioid therapy is used for pain management (e.g., treatment, amelioration, or prevention of pain). In another embodiment, opioid therapy is used to treat, prevent, or ameliorate opioid-induced adverse pharmacodynamic responses, such as euphoria, bowel dysfunction (e.g., constipation, decreased gastric emptying, abdominal cramps, abdominal distension, delayed gastrointestinal transit), nausea, vomiting, somnolence, dizziness, respiratory depression, headache, dry mouth, sedation, sweating, weakness, hypotension, dysphoria, delirium, miosis, pruritus, urticaria, urinary retention, hyperalgesia, allodynia, physical dependence, and tolerance. In a separate embodiment, opioid therapy may be used to treat diarrhea, cough, anxiety (e.g., caused by tachypnea), and opioid dependence. In another embodiment, opioid therapy may be used to treat, prevent or reduce opioid withdrawal.

As used herein, the term "Oxy" refers to oxycodone.

Synthesis of Compounds of the disclosure

In view of this disclosure, the compounds of the present disclosure may be prepared using methods known to those skilled in the art or by the illustrative methods shown in the following schemes. For example, the compounds of the present disclosure can be prepared as shown in scheme a and scheme B below. Other synthetic methods are described and illustrated in the working examples set forth below.

Scheme A

A compound of formula IV (wherein R³¹Is hydrogen or OH and R¹、R⁴And R⁵As defined above for formula I) can be prepared by reacting compound A (wherein R is³¹Hydrogen or OH and R¹And R⁴As defined above for formula I) is first prepared by mixing with lithium bis (trimethylsilyl) amide in a suitable polar aprotic solvent such as Tetrahydrofuran (THF) at about-70 ℃ to about-80 ℃, and preferably at about-78 ℃. The reaction mixture was then allowed to warm to room temperature and stirring continued at room temperature for about 30 minutes to about 1 hour. The reaction mixture is then re-cooled to a temperature of from about-70 ℃ to about-80 ℃, and preferably to about-78 ℃, and the appropriate formula (R)⁵CO)₂Anhydrides of O or of the formula R⁵Adding a reagent of C (═ O) X to the mixture, wherein R is⁵As defined above for formula I, and X is a suitable leaving group, such as Cl.

In another embodiment, the compound of formula IV (wherein R is³¹Is hydrogen) is prepared by the process of scheme a. In another embodiment, the compound of formula IV (wherein R is³¹Is OH) Prepared by the method of scheme a.

In another embodiment, in scheme a, compound a is oxycodone. In another embodiment, the anhydride in step 2) is acetic anhydride to obtain 6-acetyl oxycodone.

A compound of formula I (wherein R²is-C (═ O) R⁵And R is³is-OC (═ O) R⁶Wherein R is⁵And R⁶Identical and as defined above for formula I) may be prepared as shown in scheme B below to obtain the compound of formula V.

Scheme B

In scheme B, R¹、R⁴And R⁵As defined above for formula I. Thus, compounds of formula V may be prepared by reacting compound B with the appropriate formula (R)⁵CO)₂Anhydrides of O or of the formula R⁵C (═ O) X, where X is a suitable leaving group, such as Cl.

Compounds of any of formulae I-III including PEG-containing substituents can be prepared, for example, as described in WO 201I/088140.

In some non-limiting embodiments, the compounds of formulas 1-VI are converted to their salts using techniques commonly known to those of ordinary skill in the art. In other embodiments, the salt is a pharmaceutically acceptable salt.

Administration of the Compounds of the disclosure

The compounds of the present disclosure may act as prodrugs, and thus exhibit one or more advantages over the parent opioid drug. For example, when inadvertently administered orally at a dose higher than the prescribed dose, the compounds of the present disclosure can be used to prevent accidental overdose by exhibiting a delayed onset of pharmacological activity. In some embodiments, when administered by a non-oral route (e.g., parenteral) that may be employed by abusers, the compounds of the present disclosure may deter abuse by substantially maintaining their chemical form as prodrugs. Thus, when administered via parenteral routes, in particular intravenous, intranasal and/or inhalation routes, which are commonly used for illicit uses, the compounds of the present disclosure discourage abuse by reducing extractability and solubility of the active opioid molecules in aqueous or alcoholic media and thereby reducing the availability of the active opioid molecules.

In some embodiments, the compounds of the present disclosure have little or a different affinity for the mu opioid receptor than the parent opioid. Under the acidic conditions of the stomach, the compounds of the present disclosure are unable to convert from the prodrug form to the parent opioid. In contrast, compounds of the present disclosure may be converted to the parent opioid from the prodrug form via enzyme-assisted hydrolysis under intestinal conditions. The gradual conversion of the compounds of the present disclosure to the parent opioid upon oral administration to a mammal should result in a gradual but delayed systemic exposure to the parent opioid as compared to direct oral administration of the parent opioid.

Opioid prodrugs that provide a step-wise conversion to the parent opioid may be less attractive to substance abusers or non-medical recreational users who search for drugs to provide an opioid with rapid euphoria. Since the conversion from the compounds of the present disclosure to the parent opioid will be slower, the onset of euphoria will likewise be slower, thereby making the compounds of the present invention less attractive to those who will attempt such non-medical use of the drug.

In many cases, opioid abuse by the oral route involves immediate release drugs, or drugs in which tampering with controlled release materials has been used to delay release and absorption of the opioid from the dosage form. Immediate release opioids generally provide pharmacologically relevant plasma concentrations, onset of therapeutic effect, and onset of euphoria in the case of recreational drug users within about 15 to 180 minutes, 15 to 120 minutes, or 15 to 90 minutes after oral administration.

The gradual conversion of the compounds of the invention to the parent opioid in the GI tract may be achieved by delaying the time to reach the pharmacologically relevant plasma concentration of oxycodone, for example by providing Lower C compared to oral, immediate release forms of opioids_maxAnd/or late T_maxBut rather to delay and thus reduce any euphoric effects otherwise produced by the opioid. Thus, in some embodiments, the dosage forms of the present invention will have a lower potential for abuse and misuse.

In certain embodiments, pharmaceutical compositions containing the compounds of the present disclosure can achieve extended release profiles of pharmaceutically active ingredients (e.g., opioid analgesics). For example, the compounds of the present invention may slowly convert to the parent opioid compound in the GI tract of a patient upon oral administration. In such cases, such pharmaceutical compositions are considered to be extended release formulations.

The extended release formulation prevents the rapid onset of the pharmacological effect and is formulated in a manner that makes the pharmaceutically active ingredient available for a prolonged period of time. In some embodiments, the compounds of the present disclosure may achieve a delayed release profile simply based on the fact that they require conversion to the parent opioid. Thus, in one embodiment, the compounds of the present disclosure may be formulated without a controlled release excipient, yet still produce a delayed release of the opioid upon oral administration.

The extended release formulation may further include formulation features, for example, by incorporating a sustained release matrix or a sustained release coating or some variation thereof, to achieve an extended release profile of one or more parent opioid compounds. Controlled release formulation techniques are well known in the art and may be used in conjunction with the present invention to achieve a particular desired release profile. In some embodiments, a parent opioid and one or more compounds of the present disclosure may be combined into a single oral dosage form, wherein the opioid provides an immediate release profile and the one or more compounds of the present invention are effective to provide an extended release profile of oxycodone. Such combined preparations may or may not further comprise a sustained-release matrix or a sustained-release coating, or some variation thereof.

The present disclosure also provides a method of treating pain in a mammal (e.g., a human patient) in need thereof, comprising administering to the mammal an effective amount of a compound of the present disclosure. In certain embodiments, the compounds of the present disclosure are administered to the mammal orally.

In one embodiment, the present disclosure provides a method of reducing the abuse potential of an opioid in a mammal in need of opioid therapy, comprising orally administering to the mammal an effective amount of a compound of the present disclosure that exhibits reduced parenteral (i.e., non-oral) bioavailability as compared to the parent opioid.

In another embodiment, the present disclosure provides a method of reducing the abuse potential of oxycodone in a mammal in need of oxycodone therapy, the method comprising orally administering to the mammal an effective amount of a compound of any one of formulae II to V, or a pharmaceutically acceptable salt or solvate thereof, wherein R is¹Is CH₃，R³/R³¹Is OH, R⁴Is CH₃And R is²is-C (═ O) R⁵And R is⁵As defined above for formula II. In another embodiment, the method comprises administering a compound selected from the group consisting of:

or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, 6-acetyl oxycodone, or a pharmaceutically acceptable salt or solvate thereof, is administered.

In another embodiment, the present disclosure provides a method of treating pain and reducing oxycodone abuse potential in a mammal in need of oxycodone therapy comprising orally administering to the mammal an effective amount of a compound of formula VI or a pharmaceutically acceptable salt or solvate thereof, wherein R is¹Is CH₃，R⁴Is CH₃And R is³is-OC (═ O) R⁶And R is⁶As defined above for formula I. In another embodiment, the method comprises administering a compound

In another embodiment, the present disclosure provides a method of treating pain and reducing the abuse potential of oxymorphone in a mammal in need of oxymorphone therapy, comprising orally administering to the mammal an effective amount of a compound of formula II or formula III, or a pharmaceutically acceptable salt or solvate thereof, wherein in the compound of formula II or formula III, R is¹Is hydrogen, R³Is OH, R⁴Is CH₃And R is²is-C (═ O) R⁵And R is⁵As defined above for formula II. Alternatively, an effective amount of a compound of formula IV or a pharmaceutically acceptable salt or solvate thereof is administered, wherein R₁Is hydrogen, R³¹Is OH, R⁴Is methyl, and R⁵As defined above for formula II.

In one embodiment, the present disclosure provides a method of treating pain and reducing the potential for hydrocodone abuse in a mammal in need of hydrocodone therapy, the method comprising orally administering to the mammal an effective amount of a compound of any one of formulas II to IV, or a pharmaceutically acceptable salt or solvate thereof, wherein R is¹Is CH₃，R³/R³¹Is H, R⁴Is CH₃And R is²is-C (═ O) R⁵And R is⁵As defined above for formula II, with the proviso that the compound is not

In one embodiment, the present disclosure provides a method of treating pain and reducing hydromorphone abuse in a mammal in need of hydromorphone therapy A method of potential comprising orally administering to the mammal an effective amount of a compound of any one of formulae II to IV, or a pharmaceutically acceptable salt or solvate thereof, wherein R¹Is H, R³Or R³¹Is H, R⁴Is CH₃And R is²is-C (═ O) R⁵And R is⁵As defined above for formula II, with the proviso that the compound is not

In one embodiment, the present disclosure provides a method of reducing the abuse potential of a parent opioid compound, comprising orally administering to the mammal an effective amount of a compound of any one of formulas I to VI, or a pharmaceutically acceptable salt or solvate thereof, with the proviso that 1) the compound is not

2) When R is¹Is unsubstituted alkyl, R³Is hydrogen and R⁴Is unsubstituted C_1-6When alkyl, then R⁵Is not optionally substituted phenyl or optionally substituted pyridyl; or

3) When R is¹Is unsubstituted alkyl, R⁴Is unsubstituted C_1-6Alkyl and R³is-OC (═ O) R⁶Then R⁵And R⁶Are not optionally substituted pyridyl. In one embodiment, the present disclosure provides a method of reducing the abuse potential of a parent opioid compound, comprising orally administering to the mammal an effective amount of a compound of any one of formulas I to VI, or a pharmaceutically acceptable salt or solvate thereof, with the proviso that the compound is not

In one embodiment, the invention is a method of achieving opioid therapy (e.g., for the treatment of pain) in a mammal in need thereof, comprising orally administering to the mammal a therapeutically effective amount of a compound of any one of formulas I-VI, or a pharmaceutically acceptable salt or solvate thereof, wherein at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or about 100% of the compound of any one of formulas I-VI, or a pharmaceutically acceptable salt or solvate thereof, is hydrolyzed to the parent opioid in the presence of pancreatin intestinal fluid at pH6.8 at 37 ℃ within about 2 hours.

In one embodiment, the present invention is a method of achieving oxycodone therapy in a mammal in need thereof, the method comprising orally administering to the mammal a therapeutically effective amount of a compound of any one of formulas II to IV, or a pharmaceutically acceptable salt or solvate thereof, wherein in the compounds of formulas II to IV, R is¹Is CH₃，R³/R³¹Is OH, R⁴Is CH₃And R is²is-C (═ O) R⁵And R is⁵As defined above for formula II, wherein at least about 10%, at least about 20%, at least about 30%, at least about 40%, or at least about 50% of the compound of any one of formulae II to IV, or a salt or solvate thereof, is hydrolyzed to oxycodone in the presence of pancreatin at ph6.8 in intestinal fluid at 37 ℃ within about 2 hours.

In a particular embodiment, the method comprises orally administering to the mammal a therapeutically effective amount of a compound of any one of formulas II to IV, or a pharmaceutically acceptable salt or solvate thereof, wherein in the compound of formulas II to IV, R¹Is CH₃，R³/R³¹Is OH, R⁴Is CH₃And R is²is-C (═ O) R⁵And R is⁵As defined above for formula II, wherein at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 10% of the compound of any one of formulas II to IV or a salt or solvate thereofAbout 70%, at least about 90%, or about 100% is hydrolyzed to oxycodone in the presence of pancreatin in intestinal fluid at pH 6.8 at 37 ℃ within about 2 hours.

In one embodiment, the method comprises orally administering 6-acetyl oxycodone, or a pharmaceutically acceptable salt thereof, wherein about 80%, about 90%, about 95%, or about 100% of the 6-acetyl oxycodone, or a salt thereof, is hydrolyzed to oxycodone in the presence of pancreatin in intestinal fluid at pH 6.8 at 37 ℃ within about 2 hours.

In another embodiment, the present disclosure provides a method of reducing the abuse potential of oxycodone in a mammal in need of oxycodone therapy comprising orally administering to the mammal an effective amount of a compound of formula VI or a pharmaceutically acceptable salt or solvate thereof, wherein R is ¹Is CH₃，R⁴Is CH₃And R is³is-OC (═ O) R⁶And R is⁶As defined above for formula I, wherein at least about 10%, at least about 20%, at least about 30%, at least about 40%, or at least about 50% of the compound of formula VI or a salt or solvate thereof is hydrolyzed to oxycodone in the presence of pancreatin in intestinal fluid at pH 6.8 at 37 ℃ within about 2 hours.

In some embodiments, the bioavailability of the parent opioid provided by any parenteral route (e.g., intravenous, intranasal, or inhalation) of a compound of any one of formulas I-VI is less than about 70%, less than about 50%, less than about 30%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% of the bioavailability of the parent opioid administered by the same route.

In other embodiments, the present disclosure provides an extended release formulation of oxycodone comprising an effective amount of

Or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable excipients or carriers thereof. The extended release formulation of oxycodone may further comprise oxycodone, or a pharmaceutically acceptable salt or solvate thereof, in an immediate release form or an extended release form, or both. The present disclosure also provides methods of using such oxycodone extended release formulations, such as methods of treating pain or methods of reducing the abuse potential of opioids in a mammal in need of opioid therapy.

The compounds of the present disclosure exhibit a relatively high degree of stability, i.e., resistance to hydrolysis, when subjected to "kitchen chemistry" that may be used by a potential abuser.

6-substituted enol esters and their use as prodrugs

The inventors have found that certain 6-substituted enol esters of formula IV as defined above are mu opioid receptor agonists and may also be used as prodrugs, i.e. they may be used for the same purpose as their parent opioid compounds. Thus, these compounds are analgesic compounds when made bioavailable from dosage forms such as, for example, transdermal, subcutaneous, intramuscular, intravenous, or parenteral dosage forms. When these 6-substituted enol esters are administered orally to a patient, they are converted to the parent opioid, such as oxycodone, in certain portions of the patient's gastrointestinal tract. Thus, formulations containing certain 6-substituted enol esters can provide mu opioid agonist function from both the prodrug of formula IV and the parent opioid for a period of time after oral administration.

In this aspect of the invention, the present disclosure provides the following specific embodiments.

{ Ia }. A compound of formula IV:

or a pharmaceutically acceptable salt or solvate thereof, wherein

R¹、R⁴And R⁵As defined above for formula I or II, and R³¹Is hydrogen or OH.

A compound according to { IIa }. as in { Ia }, or a pharmaceutically acceptable salt or solvate thereof, wherein

R⁷Selected from the group consisting of: hydrogen and C_1-6An alkyl group;

m is an integer between 1 and 9;

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

PEG is an ethylene oxide unit or oligomer having from 2 to about 10 ethylene oxide subunits, with the proviso that the compound is not

{ IIIa }. As rightThe compound of claim { IIa }, or a pharmaceutically acceptable salt or solvate thereof, wherein R¹Is H or unsubstituted C_1-6Alkyl, and R⁴Is unsubstituted C_1-6An alkyl group.

{ IVa }. the compound of claim { IIa } or { IIIa } or a pharmaceutically acceptable salt thereof, wherein R³Is OH.

{ Va }. A compound as described in any one of { IIa } - { IVa }, or a pharmaceutically acceptable salt or solvate thereof, wherein R is¹And R⁴Is methyl.

{ VIa }. the compound of any one of { IIa } - { Va }, or a pharmaceutically acceptable salt thereof, wherein R is⁵Is unsubstituted C_1-6An alkyl group.

{ VIIa }. the compound of any one of { IIa } - { VIa }, or a pharmaceutically acceptable salt thereof, wherein R is⁵Is methyl.

A compound according to any one of { IIa } - { Va }, or a pharmaceutically acceptable salt thereof, wherein R is⁵Is unsubstituted C_7-12An alkyl group.

A compound according to any one of { IIa } - { Va } and { VIIIa }, or a pharmaceutically acceptable salt thereof, wherein R is⁵Is unsubstituted heptyl, octyl or nonyl.

{ Xa }. the compound of any one of { IIa } - { Va } and { VIIIa }, or a pharmaceutically acceptable salt thereof, wherein R is⁵Is unsubstituted decyl, undecyl or dodecyl.

{ XIa }. the compound of { Xa } or a pharmaceutically acceptable solvate thereof, wherein R⁵Is an undecyl group.

A compound according to any one of { IIa } - { Va }, or a pharmaceutically acceptable salt thereof, wherein

R⁵Selected from the group consisting of: -CH₂-O-(CH₂CH₂O)_m-R⁷、-O-(CH₂CH₂O)_n-R⁷and-NH- (CH)₂CH₂O)_p-R⁷；

R⁷Is hydrogen or C_1-4An alkyl group;

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.

{ XIIIa }. the compound of any one of { IIa } - { Va } and { XIIa }, or a pharmaceutically acceptable salt thereof, wherein R is⁷Is hydrogen or methyl.

A compound according to any one of { IIa } - { Va } and { XIIa }, or a pharmaceutically acceptable salt thereof, wherein R is⁵is-CH₂-O-(CH₂CH₂O)_m-R⁷。

A compound as described in any one of { IIa } - { Va } and { XIIa } - { XIVa }, or a pharmaceutically acceptable salt thereof, wherein m is 1, 2 or 3.

{ XVIa }. A compound as described by { XVa }, or a pharmaceutically acceptable salt thereof, wherein m is 2.

A compound as described in any one of { XIVa } - { XVIa }, or a pharmaceutically acceptable salt or solvate thereof, wherein R is⁷Is methyl.

A compound according to any one of { Ia } and { IIa } - { VIIa }, which is

Or a pharmaceutically acceptable salt or solvate thereof.

{ XIXa }. the compound according to { XVIIIa }, which is

Or a pharmaceutically acceptable salt or solvate thereof.

{ XXa }. the compound according to { IIa }, which is

Or a pharmaceutically acceptable salt or solvate thereof.

{ XXIa }. a pharmaceutical composition comprising a compound as defined in any one of { Ia } - { XXa }, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

{ XXIIa }. a composition comprising one or more compounds as described in { Ia } - { XXa }, or a pharmaceutically acceptable salt or solvate thereof, and at least one parent opioid.

{ XXIIIa }. The composition of { XXIIa }, comprising about 0.1 wt% to about 30 wt% of the at least one parent opioid.

(XXIVa) a composition as described in { XXIIa } or { XXIIIa } comprising from about 1 wt% to about 20 wt% of the at least one parent opioid.

A composition as described in any one of { XXIIa } - { XXIVa }, wherein the at least one parent opioid is oxycodone.

{ XXVIa }. an oral formulation comprising a therapeutically effective amount of a composition as described in any one of { XXIIa } - { XXVa }.

{ XXVIIa }. A method of treating or preventing a disorder responsive to modulation of one or more opioid receptors in a patient, comprising administering to a patient in need of such treatment or prevention an effective amount of a compound as described in any one of { Ia } - { XXa }, or a pharmaceutically acceptable salt or solvate thereof.

{ XXVIIIa }. The method as described in { XXVIIa }, wherein the disorder is pain.

{ XXIXa }. a method of treating, ameliorating or preventing pain in a patient, the method comprising administering to a patient in need of such treatment, amelioration or prevention an effective amount of a compound as described in any one of { Ia } - { XXa }, or a pharmaceutically acceptable salt or solvate thereof.

{ XXXA }. methods as described in { XXIXa }, wherein the methods are used to treat pain.

{ XXXIIa }. the method as { XXXA }, wherein the pain is acute pain, chronic pain or surgical pain.

{ XXXIIa }. the method as { XXXIIa }, wherein the pain is chronic pain.

{ XXXIIIa }. The method of { XXXIIa }, wherein the chronic pain is neuropathic pain, post-surgical pain or inflammatory pain.

{ XXXIVa }. a method of slowing the onset of opioid activity in a mammal in need of opioid therapy, the method comprising orally administering to the mammal a therapeutically effective amount of a compound or mixture of compounds according to any one of { Ia } - { XXa }, or a pharmaceutically acceptable salt or solvate thereof.

{ XXXVa }. a method of treating a disorder responsive to modulation of one or more opioid receptors and delaying the onset of opioid activity in a mammal in need of opioid therapy, comprising orally administering to the mammal a therapeutically effective amount of a compound or mixture of compounds according to any one of { Ia } - { XXa }, or a pharmaceutically acceptable salt or solvate thereof. In certain embodiments, the method further comprises one or more parent opioid compounds, wherein the total amount of the compound of the present disclosure and the parent opioid compound comprise the therapeutically effective amount.

{ XXXVIa }. methods as described in { XXXIVa } or { XXXVa }, further comprising co-administration of one or more other therapeutic agents.

{ XXXVIa }. the method of { XXXVIa }, wherein the one or more additional therapeutic agents are one or more non-steroidal anti-inflammatory agents.

{ XXXVIIa }. the method of { XXXVIa }, wherein the one or more additional therapeutic agents are one or more opioid agonists.

{ XXXIXa }. the method of { XXXVIa }, wherein the one or more additional therapeutic agents are one or more opioid antagonists.

Short-chain 14-substituted enol esters and their use as prodrugs

The inventors have discovered that certain 14-substituted enol esters of formula VI having a short-chain substituent at position 14 act as mu opioid receptor agonists and are useful as prodrugs. Thus, these compounds are analgesic compounds when made bioavailable from dosage forms such as, for example, transdermal, subcutaneous, intramuscular, intravenous, or parenteral dosage forms. When the prodrugs are delivered orally to a patient and made bioavailable only in the lower gastrointestinal tract of the patient, they are converted over time to the parent opioid, such as oxycodone, thereby providing the mu opioid agonist function from both the prodrug of formula VI and the parent opioid.

In this aspect of the invention, the present disclosure provides the following specific embodiments.

{ Ib }. a compound of formula VI:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

R¹is H; c optionally substituted by 1, 2 or 3 substituents_1-6Alkyl, each of said substituents being independently selected from the group consisting of: hydroxy, halo (C)_1-4) Alkyl, amino, C_1-4Alkylamino radical, di (C)_1-4) Alkylamino, carboxyl, C_1-4Alkoxy and C_1-4An alkoxycarbonyl group; or-PEG-R ⁷；

R³is-OC (═ O) R⁶Wherein R is⁶Selected from the group consisting of: unsubstituted C_1-4Alkyl, unsubstituted C_2-4Alkenyl, unsubstituted C_2-4Alkynyl or-CH₂-O-(CH₂CH₂O)_m-R⁷；

m is 1;

R⁷selected from the group consisting of: hydrogen and C_1-6An alkyl group; and is

PEG is one ethylene oxide unit or oligomer having 2 to about 10 ethylene oxide subunits,

with the proviso that said compound is not

{ IIb }. The compound of { Ib }, or a pharmaceutically acceptable salt or solvate thereof, wherein R is⁶Is unsubstituted methyl, ethyl, propyl or butyl.

{ IIIb }. The compound of { Ib }, or a pharmaceutically acceptable salt thereof, wherein R⁶Is unsubstituted C_2-4Alkenyl, unsubstituted C_2-4Alkynyl or-CH₂-O-CH₂CH₂O-R⁷(ii) a And R is⁷Selected from the group consisting of: hydrogen or methyl.

A compound according to any one of { IVb } - { IIIb }, or a pharmaceutically acceptable salt or solvate thereof, wherein R is ¹Is H or unsubstituted C_1-6Alkyl, and R⁴Is unsubstituted C_1-6An alkyl group.

{ Vb }. the compound of any one of { Ib } - { IVb }, or a pharmaceutically acceptable salt or solvate thereof, wherein R₁And R⁴Is methyl.

{ VIb }. Compound as { Vb }, wherein R⁶Is unsubstituted ethyl, propyl or butyl.

{ VIIb }. a pharmaceutical composition comprising a compound having formula VI:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

R¹is H; c optionally substituted by 1, 2 or 3 substituents_1-6Alkyl, each of said substituents being independently selected from the group consisting of: hydroxy, halo (C)_1-4) Alkyl, amino, C_1-4Alkylamino radical, di (C)_1-4) Alkylamino, carboxyl, C_1-4Alkoxy and C_1-4An alkoxycarbonyl group; or-PEG-R⁷；

R³is-OC (═ O) R⁶Wherein R is⁶Selected from the group consisting of: unsubstituted C_1-4Alkyl, unsubstituted C_2-4Alkenyl, unsubstituted C_2-4Alkynyl or-CH₂-O-(CH₂CH₂O)_m-R⁷；

m is 1;

R⁷selected from the group consisting of: hydrogen and C_1-6An alkyl group; and is

PEG is one ethylene oxide unit or oligomer having 2 to about 10 ethylene oxide subunits,

and one or more pharmaceutically acceptable carriers.

{ VIIIb }. The pharmaceutical composition of { VIIb }, comprising a compound of any one of { Ib } - { VIb }, or a pharmaceutically acceptable salt thereof.

{ IXb }. A pharmaceutical composition as described in { VIIb }, comprising

Or a pharmaceutically acceptable salt or solvate thereof.

A pharmaceutical composition according to any one of { VIIb } - { IXb }, further comprising at least one parent opioid.

{ XIb }. The pharmaceutical composition as described in { Xb }, which comprises from about 0.1% to about 30% of the at least one parent opioid.

A pharmaceutical composition as described in { Xb } or { XIb } comprising from about 1 wt% to about 20 wt% of the at least one parent opioid.

{ XIIIb }. the pharmaceutical composition of any one of { Xb } - { XIIb }, wherein the at least one parent opioid is oxycodone.

The pharmaceutical composition of any one of { XIVb }. the composition is formulated for oral dosage form, as described in { VIIb } - { XIIIb }.

{ XVb }. A composition comprising one or more compounds as described in { Ib } - { VIb }, or a pharmaceutically acceptable salt or solvate thereof, and at least one parent opioid.

{ XVIb }. the composition as described in { XVb }, which comprises from about 0.1 wt% to about 30 wt% of the at least one parent opioid.

(XVIIb.) a composition as described in { XVb } or { XVIb } comprising from about 1 wt% to about 20 wt% of the at least one parent opioid.

A composition as described in any one of { XVb } - { XVIIIb }, wherein the at least one parent opioid is oxycodone.

{ XIXb }. an oral formulation comprising a therapeutically effective amount of a composition as described in any one of { XVb } - { XVIIIb }.

A method of treating or preventing a disorder responsive to modulation of one or more opioid receptors in a patient, comprising administering to a patient in need of such treatment or prevention an effective amount of a compound having formula VI:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

R³is-OC (═ O) R⁶Wherein R is⁶Selected from the group consisting of: unsubstituted C _1-4 alkyl, unsubstituted C_2-4Alkenyl, unsubstituted C_2-4Alkynyl or-CH₂-O-(CH₂CH₂O)_m-R⁷；

m is 1;

R⁷selected from the group consisting of: hydrogen and C_1-6An alkyl group; and is

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

A method as described in { XXIb }, wherein a compound as described in any one of { Ib } - { VIb }, or a pharmaceutically acceptable salt or solvate thereof, is administered.

{ XXIIb }. the process as described in { XXb }, wherein the compound is

Or a pharmaceutically acceptable salt or solvate thereof.

A method as described in any one of { XXIIIb } - { XXIIb }, wherein the disorder is pain.

{ XXIVb }. a method of treating, ameliorating, or preventing pain in a patient, the method comprising administering to a patient in need of such treatment, amelioration, or prevention an effective amount of a compound having the compound of formula VI:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

R¹is H; c optionally substituted by 1, 2 or 3 substituents_1-6Alkyl, each of said substituents being independently selected from the group consisting of: hydroxy, halo (C)_1-4) Alkyl, amino, C_1-4Alkylamino radical, di (C)_1-4) Alkylamino, carboxyl, C_1-4Alkoxy and C_1-4An alkoxycarbonyl group; or-PEG-R⁷；

R³is-OC (═ OC)O)R⁶Wherein R is⁶Selected from the group consisting of: unsubstituted C_1-4Alkyl, unsubstituted C_2-4Alkenyl, unsubstituted C_2-4Alkynyl or-CH₂-O-(CH₂CH₂O)_m-R⁷；

m is 1;

R⁷selected from the group consisting of: hydrogen and C_1-6An alkyl group; and is

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

A method as described in { XXVb }. the method as described in { XXIVb }, wherein a compound as described in any of { Ib } - { VIb }, or a pharmaceutically acceptable salt or solvate thereof, is administered to a patient in need of such treatment, amelioration or prophylaxis.

{ XXVIb }. the process as described in { XXIVb }, wherein the compound is

Or a pharmaceutically acceptable salt or solvate thereof.

A method as described in any one of { XXIVb } - { XXVIb }, wherein the method is for the treatment of pain.

{ XXVIIIb } the method of { XXVIIb }, wherein the pain is acute pain, chronic pain, or surgical pain.

{ XXIXb }. The method as described in { XXVIIIb }, wherein the pain is chronic pain.

{ XXXB }. methods as described in { XXIXb }, wherein the chronic pain is neuropathic pain, post-surgical pain, or inflammatory pain.

{ XXXIb }. a method of slowing the onset of opioid activity in a mammal in need of opioid therapy, the method comprising orally administering to the mammal a therapeutically effective amount of a compound or mixture of compounds according to any one of { Ib } - { VIIIc }, or a pharmaceutically acceptable salt or solvate thereof.

{ XXXIIib }. A method of treating a disorder responsive to modulation of one or more opioid receptors and delaying the onset of opioid activity in a mammal in need of opioid therapy, the method comprising orally administering to the mammal a therapeutically effective amount of a compound or mixture of compounds according to any one of { Ib } - { VIIIb }, or a pharmaceutically acceptable salt or solvate thereof. In certain embodiments, the method further comprises one or more parent opioid compounds, wherein the total amount of the compound of the present disclosure and the parent opioid compound comprise the therapeutically effective amount.

{ XXXIIIb }. The method as described in { XXXIIb } or { XXXIIIb }, further comprising co-administering one or more further therapeutic agents.

{ XXXIVb }. the method of { XXXIIIb }, wherein the one or more other therapeutic agents are one or more non-steroidal anti-inflammatory agents.

{ XXXVb }. the method of { XXXIIIb }, wherein the one or more other therapeutic agents is one or more opioid agonists.

{ XXXVIb }. the method of { XXXIIIb }, wherein the one or more additional therapeutic agents are one or more opioid antagonists.

Medium chain 6, 14-disubstituted enol esters and their use as prodrugs

The inventors have found that certain 6, 14-disubstituted enol esters of formula II having a medium length chain as a substituent at both positions 6 and 14 act as mu opioid receptor agonists and may also act as prodrugs. Thus, these compounds are analgesic compounds when made bioavailable from dosage forms such as, for example, transdermal, subcutaneous, intramuscular, intravenous, or parenteral dosage forms. When the prodrugs are made bioavailable only in the lower gastrointestinal tract of a patient, they are converted over time to the parent opioid, such as oxycodone, thereby providing the mu opioid agonist function from both the prodrug of formula II and the parent opioid.

In this aspect of the invention, the present disclosure provides the following specific embodiments.

{ Ic }. A compound of formula II:

a pharmaceutically acceptable salt or solvate thereof, wherein:

R¹is H; c optionally substituted by 1, 2 or 3 substituents_1-6Alkyl, each of said substituents being independently selected from the group consisting of: hydroxy, halo (C)_1-4) Alkyl, amino, C_1-4Alkylamino radical, di (C)_1-4) Alkylamino, carboxyl, C_1-4Alkoxy and C _1-4An alkoxycarbonyl group; or-PEG-R⁷；

R²is-C (═ O) R⁵And R is³is-OC (═ O) R⁶Wherein

R⁷Selected from the group consisting of: hydrogen and C_1-6An alkyl group;

m is 2 or 3;

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

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

{ IIc }. The compound of { Ic }, or a pharmaceutically acceptable salt or solvate thereof, wherein R⁵And R⁶Each independently selected from the group consisting of: heptyl, octyl, nonyl, -CH₂-O-(CH₂CH₂O)_m-R⁷、-O-(CH₂CH₂O)_n-R⁷and-NH- (CH)₂CH₂O)_p-R⁷(ii) a Wherein R is⁷Is hydrogen or C_1-4An alkyl group.

{ IIIc }. Compounds as described in { Ic } or { IIc }, wherein R ⁵And R⁶Is the same, having formula V:

or a pharmaceutically acceptable salt or solvate thereof.

{ IVc }. the compound according to { IIIc }, or a pharmaceutically acceptable salt or solvate thereof, wherein R⁵is-CH₂-O-(CH₂CH₂O)_m-R⁷Wherein R is⁷Is hydrogen or methyl.

{ Vc }. Compounds as described in { Ic } or { IIc } or pharmaceutically acceptable salts or solvates thereof, wherein R⁵And R⁶Is different.

{ VIc }. A compound as described in any one of { Ic } - { Vc }, or a pharmaceutically acceptable salt or solvate thereof, wherein R is¹Is H or unsubstituted C_1-6Alkyl, and R⁴Is unsubstituted C_1-6An alkyl group.

{ VIIc }. A compound as described in any one of { Ic } - { VIc }, or a pharmaceutically acceptable salt or solvate thereof, wherein R is₁And R⁴Is methyl.

A compound of { VIIIc }. as { Ic } or { IIIc }, which is

Or a pharmaceutically acceptable salt or solvate thereof.

{ IXc }. A pharmaceutical composition comprising a compound of any one of { Ic } - { VIIic }, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

{ Xc }. a composition comprising one or more compounds of { Ic } - { VIIIc }, or a pharmaceutically acceptable salt or solvate thereof, and at least one parent opioid.

{ XIc }. The composition as { Xc }, comprising about 0.1 wt% to about 30 wt% of the at least one parent opioid.

{ XIic }. The composition as { Xc } or { XIc } comprises from about 1 wt% to about 20 wt% of the at least one parent opioid.

A composition as defined in any one of { Xc } - { XIIc }, wherein the at least one parent opioid is oxycodone.

{ XIVc }. an oral formulation comprising a therapeutically effective amount of a composition as described in any one of { Xc } - { XIVc }.

{ XVC }. A method of treating or preventing a disorder responsive to modulation of one or more opioid receptors in a patient, the method comprising administering to a patient in need of such treatment or prevention an effective amount of a compound as described in any one of { Ic } - { VIIic }, or a pharmaceutically acceptable salt or solvate thereof.

{ XVIc }. the method of { XVc }, wherein the disorder is pain.

{ XVIic }. A method of treating, ameliorating or preventing pain in a patient, the method comprising administering to a patient in need of such treatment, amelioration or prevention an effective amount of a compound as described in any one of { Ic } - { VIIic }, or a pharmaceutically acceptable salt or solvate thereof.

{ XVIIc }. The method of { XVIic }, wherein the method is for the treatment of pain.

The method of { XIXc }. the method of { XVIIIc }, wherein the pain is acute pain, chronic pain, or surgical pain.

{ XXc }. methods as described in { XIXc }, wherein the pain is chronic pain.

{ XXic }. methods as described in { XXc }, wherein the chronic pain is neuropathic pain, post-surgical pain, or inflammatory pain.

A method of slowing the onset of opioid activity in a mammal in need of opioid therapy, the method comprising orally administering to the mammal a therapeutically effective amount of a compound or mixture of compounds according to any one of { Ic } - { VIIIc }, or a pharmaceutically acceptable salt or solvate thereof.

A method of treating a disorder responsive to modulation of one or more opioid receptors and delaying the onset of opioid activity in a mammal in need of opioid therapy, comprising orally administering to the mammal a therapeutically effective amount of a compound or mixture of compounds according to any one of { Ic } - { VIIIc }, or a pharmaceutically acceptable salt or solvate thereof. In certain embodiments, the method further comprises one or more parent opioid compounds, wherein the total amount of the compound of the present disclosure and the parent opioid compound comprise the therapeutically effective amount.

A method as described in { XXIIc } or { XXIIIc }, further comprising co-administering one or more additional therapeutic agents.

{ XXVc }. the method as described in { XXIVc }, wherein the one or more other therapeutic agents are one or more non-steroidal anti-inflammatory agents.

{ XXVIc }. methods as described in { XXIVc }, wherein the one or more other therapeutic agents are one or more opioid agonists.

{ XXVIIc }. the method as described in { XXIVc }, wherein the one or more additional therapeutic agents are one or more opioid antagonists.

Long chain 6, 14-disubstituted enol esters and their use as prodrugs to deter abuse

The inventors have found that certain 6, 14-disubstituted compounds of formula II having long chains as substituents in both the 6-and 14-positionsThe enol esters of (a) provide mu opioid receptor agonist function only upon conversion in the lower intestine to the corresponding 6-substituted compounds and the parent opioid. In particular, the inventors found that 6, 14-bis-lauroyl oxycodone provides mu opioid agonist function when converted to 6-lauroyl oxycodone and oxycodone in the lower intestine of patients. Thus, a compound of formula II (wherein R is as defined above)⁵And R⁶Both long) are useful as opioid prodrugs that deter abuse. When these prodrugs are made bioavailable only in the lower gastrointestinal tract of a patient, the enol ester at position 14 will hydrolyze over time to a 6-substituted enol ester compound and further to the parent opioid, such as oxycodone, thereby providing the mu opioid agonist function from both the 6-substituted enol ester prodrug of formula IV and the parent opioid as discussed above.

In this aspect of the invention, the present disclosure provides the following specific embodiments.

{ Id }. a compound of formula II:

a pharmaceutically acceptable salt or solvate thereof, wherein:

R¹is H; c optionally substituted by 1, 2 or 3 substituents_1-6Alkyl, each of said substituents being independently selected from the group consisting of: hydroxy, halo (C)_1-4) Alkyl, amino, C_1-4Alkylamino radical, di (C)_1-4) Alkylamino, carboxyl, C_1-4Alkoxy and C_1-4An alkoxycarbonyl group; or-PEG-R⁷；

R²is-C (═ O) R⁵And R is³is-OC (═ O) R⁶Wherein

R⁷Selected from the group consisting of: hydrogen and C _1-6An alkyl group;

m is an integer between 4 and 9;

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

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

{ IId }. The compound of { Id }, or a pharmaceutically acceptable salt or solvate thereof, wherein R⁵And R⁶Each independently selected from the group consisting of: decyl, undecyl and dodecyl.

{ IIId }. Compounds as described in { Id } or { IId }, wherein R⁵And R⁶Is the same, having formula V:

or a pharmaceutically acceptable salt or solvate thereof.

{ IVd }. The compound of { IIId }, or a pharmaceutically acceptable salt or solvate thereof, wherein R⁵Is an undecyl group.

{ Vd }. A compound as described in { Id } or { IId }, or a pharmaceutically acceptable salt or solvate thereof, wherein R⁵And R⁶Is different fromIn (1).

{ VId }. A compound as defined in any one of { Id } - { Vd }, or a pharmaceutically acceptable salt or solvate thereof, wherein R is¹Is H or unsubstituted C_1-6Alkyl, and R⁴Is unsubstituted C_1-6An alkyl group.

A compound according to any one of { Id } - { VId }, or a pharmaceutically acceptable salt or solvate thereof, wherein R is₁And R⁴Is methyl.

A compound of { VIIId }. the compound being { Id } or { IIId }, the compound being

Or a pharmaceutically acceptable salt or solvate thereof.

{ IXd }. A pharmaceutical composition comprising a compound of any one of { Id } - { VIIId }, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

{ Xd }. A composition comprising one or more compounds described by { Id } - { VIIId }, or a pharmaceutically acceptable salt or solvate thereof, and at least one parent opioid.

{ XId }. The composition as { Xd }, comprising about 0.1 wt% to about 30 wt% of the at least one parent opioid.

A composition as described in { Xd } or { XId }, said composition comprising from about 1 wt% to about 20 wt% of the at least one parent opioid.

A composition as defined in any one of { Xd } - { XIId }, wherein the at least one parent opioid is oxycodone.

{ XIVd }. an oral formulation comprising a therapeutically effective amount of a composition as described in any one of { Xd } - { XIVd }.

{ XVd }. A method of treating or preventing a disorder responsive to modulation of one or more opioid receptors in a patient, the method comprising administering to a patient in need of such treatment or prevention an effective amount of a compound as described in any one of { Id } - { VIIId }, or a pharmaceutically acceptable salt or solvate thereof.

{ XVId }. the method of { XVd }, wherein the disorder is pain.

{ XVId }. A method of treating, ameliorating or preventing pain in a patient, the method comprising administering to a patient in need of such treatment, amelioration or prevention an effective amount of a compound as described in any one of { Id } - { VIId }, or a pharmaceutically acceptable salt or solvate thereof.

{ XVIId }. The method as { XVIid }, wherein the method is for the treatment of pain.

{ XIXd }. The method of { XVIId }, wherein the pain is acute pain, chronic pain, or surgical pain.

{ XXd }. methods as described in { XIXd }, wherein the pain is chronic pain.

The method of { XXId }. the method of { XXd }, wherein the chronic pain is neuropathic pain, post-surgical pain, or inflammatory pain.

A method of treating or preventing pain and delaying the onset of activity in a mammal in need of opioid therapy, the method comprising orally administering to the mammal a therapeutically effective amount of a compound or mixture of compounds according to any one of { Id } - { VIIId }, or a pharmaceutically acceptable salt or solvate thereof. In certain embodiments, the method further comprises one or more parent opioid compounds, wherein the total amount of the compound of the present disclosure and the parent opioid compound comprise the therapeutically effective amount.

A method as described in { XXIId } or { XXIIId }, the method comprising orally administering a compound or mixture of compounds having formula V:

or a pharmaceutically acceptable salt or solvate thereof, wherein

R¹Is H or unsubstituted C_1-6An alkyl group;

R⁴is unsubstituted C_1-6An alkyl group; and is

R⁵Is decyl, undecyl or dodecyl.

{ XXVd }. the method as described in { XXIVd }, wherein R¹Is H or methyl, and R⁴Is methyl.

{ XXVId }. methods as described in { XXIVd } or { XXVd }, where R is⁵Is an undecyl group.

A method as described in any one of { XXIId } - { XXVId }, further comprising co-administering one or more additional therapeutic agents.

The method of { XXVIId }. the method of { XXVIId }, wherein the one or more additional therapeutic agents are one or more non-steroidal anti-inflammatory agents.

{ XXIXd }. The method as described in { XXVIId }, wherein the one or more other therapeutic agents are one or more opioid agonists.

{ XXXD }. the method as described in { XXVIId }, wherein the one or more additional therapeutic agents are one or more opioid antagonists.

The method of any one of { XXXId }. the method of any one of { XXIVd } - { XXVId }, wherein the compound or mixture of compounds is administered in a single dosage form further comprising an effective amount of the parent opioid.

Long-chain 14-substituted enol esters and their use as partial agonists and partial antagonists

The inventors have discovered that certain 14-substituted enol esters of formula VI having a long-chain substituent at position 14 act as partial mu opioid receptor agonists and partial mu opioid receptor antagonists, such as 16-lauroyl oxycodone. Thus, these long chain substituted enol esters are useful in methods of treating or preventing an opioid-induced adverse pharmacodynamic response induced by administration of another opioid. Opioid-induced adverse pharmacodynamic responses include, for example, bowel dysfunction, nausea, vomiting, lethargy, dizziness, respiratory depression, headache, dry mouth, sedation, sweating, asthenia, hypotension, dysphoria, delirium, miosis, pruritus, urticaria, urinary retention, hyperalgesia, allodynia, physical dependence, and tolerance. In one embodiment, the opioid-induced adverse pharmacodynamic response is selected from the group consisting of: constipation, diarrhea, withdrawal from alcohol addiction and withdrawal from drug addiction.

In this aspect of the invention, the present disclosure provides the following specific embodiments.

{ Ie }. a compound of formula VI:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

R¹is H; c optionally substituted by 1, 2 or 3 substituents_1-6Alkyl, each of said substituents being independently selected from the group consisting of: hydroxy, halo (C)_1-4) Alkyl, amino, C_1-4Alkylamino radical, di (C)_1-4) Alkylamino, carboxyl, C_1-4Alkoxy and C_1-4An alkoxycarbonyl group; or-PEG-R⁷；

R⁷Selected from the group consisting of: hydrogen and C_1-6An alkyl group;

m is an integer between 4 and 9;

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

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

{ IIe }. A compound as described in { Ie }, or a pharmaceutically acceptable salt or solvate thereof, wherein R is⁶Is decyl, undecyl or dodecyl.

{ IIIe }. Compounds as described in { Ie } or { IIe }, or pharmaceutically acceptable salts or solvates thereof, wherein R is¹Is H or unsubstituted C_1-6Alkyl, and R⁴Is unsubstituted C_1-6An alkyl group.

A compound according to any one of { IVe } - { IIIe }, or a pharmaceutically acceptable salt or solvate thereof, wherein R is⁶Is an undecyl group.

{ Ve }. A compound as described in any one of { Ie } - { IVe }, or a pharmaceutically acceptable salt or solvate thereof, wherein R is₁And R⁴Is methyl.

{ VIe }. A compound as described in { Ie }, which is

Or a pharmaceutically acceptable salt or solvate thereof.

{ VIIe }. a pharmaceutical composition comprising a compound as defined in any one of { Ie } - { VIe }, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

{ VIIIe }. a composition comprising one or more compounds as described in { Ie } - { VIe }, or a pharmaceutically acceptable salt or solvate thereof, and at least one parent opioid.

{ IXe }. The composition as { VIIIe }, comprising from about 0.1 wt% to about 30 wt% of the at least one parent opioid.

A composition as described in { VIIIe } or { IXe } comprising from about 1 wt% to about 20 wt% of the at least one parent opioid.

{ XIe }. the composition of any one of { VIIIe } - { Xe }, wherein the at least one parent opioid is oxycodone.

{ XIIe }. an oral formulation comprising a therapeutically effective amount of a composition as described in any one of { VIIIe } - { XIe }.

{ XIIIE }. A method of treating or preventing a disorder responsive to modulation of one or more opioid receptors in a patient, the method comprising administering to a patient in need of such treatment or prevention an effective amount of a compound as described in any one of { Ie } - { VIe }, or a pharmaceutically acceptable salt or solvate thereof.

{ XIVe }. The method of { XIIIE }, wherein the disorder is constipation, diarrhea, alcohol addiction withdrawal, or drug addiction withdrawal.

{ XVe }. A method of treating or preventing an opioid-induced adverse pharmacodynamic response, the method comprising administering to a patient in need thereof an effective amount of a compound as described in any one of { Ie } - { VIe }, or a pharmaceutically acceptable salt or solvate thereof, to treat or prevent the adverse pharmacodynamic response induced by administration of another opioid.

{ XVIE }. A method of treating, ameliorating or preventing constipation, diarrhea, alcohol addiction withdrawal or drug addiction withdrawal in a patient, the method comprising administering to a patient in need of such treatment or prevention an effective amount of a compound as described in any one of { Ie } - { VIe }, or a pharmaceutically acceptable salt or solvate thereof.

Pharmaceutical composition

The present invention further relates to pharmaceutical compositions comprising a therapeutically effective amount of at least one compound of the present disclosure and a pharmaceutically acceptable carrier. The pharmaceutical compositions of the present invention may also contain one or more other compatible pharmaceutically active agents, if desired.

Pharmaceutical compositions within the scope of the present invention include all compositions wherein a compound of the present disclosure is present in an amount effective (via conversion to the parent opioid) to achieve its intended purpose. While individual needs will vary, it is within the skill of the art in light of this disclosure to determine the optimal ranges for effective amounts of each component. In some embodiments, the compounds of the present disclosure may be administered to a mammal. In some embodiments, the mammal is a human, and preferably a patient being treated for an opioid-treatable condition (e.g., pain). As will be apparent from this disclosure, the compounds of the present disclosure and mixtures thereof are preferably administered orally. In some embodiments, the compounds of the present disclosure are administered at a dose or molar equivalent of 0.1 to 5mg/kg of body weight of the mammal being treated.

In some embodiments, a unit oral dose comprises between 5mg and 640mg, between 5mg and 320mg, between 5mg and 200mg, between 5mg and 160mg, between 5mg and 100mg, between 5mg and 50mg, between 5mg and 25mg, between 5mg and 20mg, and between 5mg and 10mg of a compound of the present disclosure, or a mixture thereof. In some embodiments, the unit oral dose is 5mg, 10mg, 20mg, 25mg, 50mg, 60mg, 80mg, 100mg, 120mg, 160mg, 320mg, or 640mg of the free compound of the present disclosure, or a molar equivalent of a pharmaceutically acceptable salt thereof.

In some embodiments, the oral dosage form is a unit oral dosage form administered every 4 hours, every 6 hours, every 8 hours, every 12 hours, or every 24 hours.

In some embodiments, a compound of the present disclosure or a mixture thereof may be administered as part of a pharmaceutical composition. In some embodiments, the pharmaceutical compositions of the present disclosure contain one or more suitable pharmaceutically acceptable carriers selected from known excipients and adjuvants to facilitate processing of the compounds into pharmaceutical dosage forms and/or to facilitate or otherwise control dissolution of the dosage forms. In a particular embodiment, the pharmaceutical compositions of the present disclosure are in orally administrable dosage forms. In some embodiments, the pharmaceutical composition is in the form of a solid oral dosage form, such as a powder, granule, tablet, pellet, multiparticulate, dragee, or capsule. In other embodiments, the pharmaceutical composition is in the form of a liquid oral dosage form, such as an oral solution, oral suspension, or oral emulsion.

In some embodiments, an oral dosage form contains 0.01% to 99%, 0.01% to 90%, 0.01% to 85%, 0.01% to 80%, or 0.01% to 75% by weight of a compound of the present disclosure or a mixture thereof, along with one or more excipients.

Orally administered pharmaceutical compositions of the present disclosure may contain one or more excipients. Suitable excipients include fillers, such as sugars (for example lactose or sucrose, mannitol, sodium saccharine or sorbitol), magnesium carbonate, cellulose preparations and/or calcium phosphates (for example tricalcium phosphate or calcium hydrogen phosphate), and binders, such as starch pastes, using, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylmethyl cellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone. If desired, disintegrating agents may be added, such as the starches mentioned above as well as carboxymethyl-starch, cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate. Auxiliaries are, above all, flow-regulating agents and lubricants, for example silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol; sweeteners, such as fructose, aspartame or saccharin; flavoring agents, such as peppermint, oil of wintergreen, or cherry; a colorant; and preservatives to provide pharmaceutically palatable preparations. In addition, dyes or pigments can be added to the tablets or dragee coatings, for example for identification or to facilitate characterization of the active compound dose combination. Further examples of suitable pharmaceutical excipients are described in Remington's pharmaceutical sciences, pp 1447-1676 (eds. Alfonso R.Gennaro, 19 th edition.1995), which is incorporated herein by reference. In one embodiment, the excipient is pharmaceutical grade.

In some embodiments, the pharmaceutical compositions of the present disclosure are manufactured in a manner that will be known in light of the present disclosure, as for example, by means of conventional mixing, granulating, dragee-making, dissolving or lyophilizing processes.

The pharmaceutical compositions of the present disclosure may be administered by any means to achieve their intended purpose. Preferably, administration is by the oral route. The dose administered and the frequency of administration will depend on the age, health, sex, medical condition and weight of the recipient, any concurrent treatment (if any), the frequency of treatment and the nature of the desired effect, among other factors.

The compounds of the present disclosure or mixtures thereof may be delivered in an immediate release system, a controlled release system, or a sustained release system. See, e.g., U.S. patent nos. 5,672,360, 5,968,551, 6,294,195, 7,270,831, and 7,514,100 for a more detailed description of controlled release or sustained release systems. Controlled Release or sustained Release systems can also be prepared by methods known in the art (see, e.g., Goodson, Medical Applications of Controlled Release, Vol.2, pp.115-138 (1984)). Also useful are compositions prepared by Langer, Science 249: 1527 other controlled release or sustained release systems as discussed in 1533 (1990).

The compounds of the present disclosure or mixtures thereof can be prepared as gastroretentive drug delivery systems that remain in the stomach or upper part of the gastrointestinal tract for controlled delivery. For a more detailed description of gastroretentive drug delivery systems, see, e.g., U.S. patent nos. 5,232,704; 7,157,100, respectively; 7,838,028, respectively; and U.S. patent application publication No. 2006/0013876. Gastric retentive drug delivery systems can also be prepared by methods known in the art (see, e.g., Sharma, N. et al, International Journal of Research in Pharmaceutical and Biomedical Sciences 2: 428-441 (2011)).

The production of tablets and granules as disclosed in U.S. patent nos. 4,167,558 and 6,090,411 may also be used. The preparation of a bilayer tablet as disclosed in U.S. patent No. 4,140,755 may also be used.

U.S. patent No. 5,169,638 contains powders of active agent, hydrocolloid, pH dependent polymer and adhesive, all of which are placed in capsules. The forms disclosed in said documents are suitable for the delivery of the compounds of the invention.

U.S. patent No. 6,635,279 discloses a mixture of polyvinyl acetate and polyvinylpyrrolidone and an excipient. These forms can be prepared by simple methods and exhibit unusual mechanical strength. The forms disclosed in said documents are suitable for delivering one or more compounds of the present disclosure.

In some embodiments, the compounds of the present disclosure are co-administered with one or more other therapeutic agents.

In some embodiments, the compounds of the present disclosure may be co-administered with one or more non-opioid analgesics. Suitable non-opioid analgesics include, but are not limited to, non-steroidal anti-inflammatory agents selected from aspirin, ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen (flubufen), ketoprofen, indoprofen, pirprofen (piroprofen), carprofen, oxaprozin, pranoprofen (pramoprofen), muoprofen (muoprofen), treprofen (trioxaprofen), suprofen, amprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, ulfenamic acid, zidometacin, acemetacin, fentiac acid, clidanac, opifenamic acid (oxypinac), mefenamic acid, meclofenamic acid, flufenamic acid, niflumic tolfenamic acid, diflunisal (diflurisal), flufenisal, piroxicam, sudoxicam, isoxicam, pharmaceutically acceptable salts thereof, and mixtures thereof. Other suitable non-opioid analgesics include, but are not limited to, salicylic acid derivatives, including, but not limited to, sodium salicylate, choline magnesium trisalicylate, salsalate, diflunisal, salicylsalicylic acid, sulfasalazine, and olsalazine; para-aminophenol derivatives, including but not limited to acetaminophen; indole and indene acetic acids including but not limited to indomethacin, sulindac and etodolac; heteroaryl acetic acids including, but not limited to tolmetin, diclofenac, and ketorolac; anthranilic acid (fenamate), including mefenamic acid and meclofenamic acid; enolic acids, including, but not limited to, oxicams (piroxicam and tenoxicam), and pyrazolidinediones (phenylbutazone and oxyphenthazone); and alkanones, including but not limited to nabumetone. For a more detailed description of non-opioid analgesics that may be co-administered with The compounds according to The present disclosure, see Paul A. Insel, analytical-Inflammatory and Analgesic and Drugs injected in The Treatment of Gout in Goodman & Gilman's The pharmaceutical Basis of Therapeutics, 617-incorporated 657(PerryB. Molinhoff and Raymond W. Ruddon eds., 9 th edition 1996), and Glen R. Hanson, analytical and Anti-Inflammatory Drugs in Remington: the Science and practice of Pharmacy, Vol.II, 1196-1221 (eds. A.R. Gelmaro, 19 th edition 1995).

In some embodiments, the compounds of the present disclosure may be co-administered with one or more opioid agonists. Suitable opioid agonists include, but are not limited to, alfentanil, allyldine, alfadine, anileridine, benzylmorphine, benzamidine, buprenorphine, butorphanol, lonicerazine, codeine, desomorphine, dextromoramide (dexromoramide), dezocine, deanylpropylamine, diamorphinone (diamorphine), dihydrocodeine, dihydromorphine, dimemethadol (dimexadol), dimemepeptanol (dimepheritol), dimethylthiodine (dimelhalambutene), moroxydemetine (dipalmitone), epizocine (eptazone), esomeptazinone (etheptazone), ethiopipramine (etheptazone), ethidium, ethylmorphine, etonilazine (etone), fentanyl, heroin, hydrocodone, hydropiperone, hydroxypiperidone (hydropiperidone), isoethidene (methadone), levomethorphanol (levorphanol), levorphanol (levorphanol), levorphanol (levorphanol), levorphanol (levorphanol), levo, Mevalon (metazocine), methadone (methadone), metoprolone (metopon), morphine, murophine (myrophine), nalbuphine, narcosine (narceine), nicomorphine (nicomorphine), norlevorphanol (norlevorphenol), normethadone (normethadone), nalprofen, normorphine, nopiperone, opium, oxycodone, oxymorphone, opiate (papaveretum), pentazocine, phenoxepinone (phenodoxone), fenoxamine (phenomophan), phenazophane (phenoxazone), phenazophane (phenoxazine), phenazosine (phenazocine), phenproperine (phenoperidine), piminodine (piminodine), piminidine (piritamide), propienazine (propertisone), meperidine (promethidine), propiveridine (propathetazine), propidine (propathetazine), pimentadine (piperadine), pamidrine (piperadine), and mixtures thereof.

In some embodiments, the compounds of the present disclosure may be co-administered with one or more anti-migraine agents. Suitable anti-migraine agents include, but are not limited to, apremipride, dihydroergotamine, dolasetron, ergocornine, ergoisoconitine, ergocarine, ergot, ergotamine, flumetrenone acetate, xylazine, lisuride, lomerizine, ergometridine oxicolone, benzthiadine, and mixtures thereof.

In some embodiments, a compound of the present disclosure may be co-administered with one or more antiemetics. Suitable antiemetics include, but are not limited to, metoclopramide (metoclopramide), domperidone, prochlorperazine, promethazine, chlorpromazine, trimethobenzamide, ondansetron, granisetron, hydroxyzine acetylleucine (acetoleucine) monoethanolamine, aripride, azasetron, phenquinamine, aceophylline, brompride, buclizine, clopride, cyclizine, dimenhydrinate, difenidol, dolasetron, meclozine, mesalamine, metopimazine, cannabirone, oxypendyl, pipamazine, scopolamine, sulpiride, tetrahydrocannabinol, thiethylperazine, thioproperazine, tropisetron, and mixtures thereof.

In some embodiments, the compounds of the present disclosure may be co-administered with one or more beta adrenergic blockers. Suitable beta adrenergic blockers include, but are not limited to, acebutolol, alprenolol, amosulolol (amosulobol), arotinolol, atenolol, bufuralol, betaxolol, bevantolol, bisoprolol, bopindoll, bucindolol, bufalol, bundanolol, braalol, bucindolol hydrochloride, bufelonolol, carpiolol, carteolol, carvedilol, celiprolol, seliprolol, celanolol, loralol, elaipranolol, metoprolol, moprolol, nadolol, naproxolol, nebivolol (nebivalol), nifedilol, nipropranolol, oxprenolol, penbutolol, pindolol, propranolol, metoprolol, tioxolol, tiaprofanolol, bexolol, byalol, etc, Talinolol, terbalol, tiliolol, timolol, toliprolol, schizalol, and mixtures thereof.

In some embodiments, the compounds of the present disclosure may be co-administered with one or more anticonvulsant agents. Suitable anticonvulsants include, but are not limited to, acetylphenylbutyric urea, abutoin, alodione, aminoglutethimide, 4-amino-3-hydroxybutyric acid, phentermine, beclomethamine, braurethan, calcium bromide, carbamazepine, cinnamylamine, clomeprazole, clonazepam, desipramide (decimide), dioxanone, dimedone, doxetazin (doxetronin), etabarbital, ethaboxidone, ethosuximide, ethionine, felbamate, floroethylsulfone, gabapentin, 5-hydroxytryptophan, lamotrigine, magnesium bromide, magnesium sulfate, mefendulin, methylphenbarbital, methamphetamine, metytoin, methethosuximide, 5-methyl-5- (3-phenanthryl) -hydantoin, 3-methyl-5-phenylhydantoin, noscapine, nitrazepam, zepam, Oxcarbazepine, mebendione, phenylacetyl urea, phenobarbital, phenylbutyryl urea, phenobarbital, phensuximide, phenylmethylbarbituric acid, phenytoin sodium, potassium bromide, pregabalin (pregabaline), primidone, pregabalin, sodium bromide, solanum, strontium bromide, succinfenib, thiothiazide, tetrodotoxin, tiagabine, topiramate, trimethadione, valproic acid, valproamide, vigabatrin, zonisamide, and mixtures thereof.

In some embodiments, the compounds of the present disclosure may be co-administered with one or more antidepressants. Suitable antidepressants include, but are not limited to, benedaline, caroxazone, citalopram, dimetaxane, fencamine, indapane, indapaine hydrochloride, nefopam, nomifensine, hydroxytryptophan, oxypertine, paroxetine, sertraline, thiepine, trazodone, benmoxine, iprochlorazine, iproniazid, isocarboxazid, niazid, otamine, otamoxiflozin, phenelzine, cotinine, rolipram, meprotiline, metrazine, mianserin, mirtazapine, aclzolam, amitriptyline, amoxapine, butraline, clomipramine, dememipramine, desipramine, dibenzepine, ditripine, doxepin, fluxipramine (fluazidine), imipramine, trimethoprim, imipramine, trimethoprim, imipramine, imi, Examples of suitable excipients include, but are not limited to, norcetin (norxiptilin), opipramol, phenthidine, propipirocin, protriptyline, quinupramine, tianeptine, trimipramine, acloninib, benactyzine, bupropion, butacetin, desolvated, duloxetine, etoperidone, febuxostat, fexofenadine, fenglutarol, fluoxetine, fluvoxamine, hematoporphyrin, hypericin, levofaxate, medroxamine, milnacipran, milnaciprin, nefazodone, oxafluocinolone, pirberalin, protripan, pirisucideanol, tamsulindac, tandospirone, trazolone, tolfencinon, toloxazalone, tranylcypromine, L-tryptophan, venlafaxine, mevinodine, ziziprasine, and mixtures thereof.

In some embodiments, a compound of the present disclosure may be combined with one or more Ca²⁺-co-administration of channel blockers. Suitable Ca²⁺Channel blockers include, but are not limited to, bepridil, clentripm, diltiazem, fendiline, gallopamil, mibedil, prenylamine, semodil, terodil, verapamil, amlodipine, aradipine, barnidipine, benidipine, cilnidipine, efonidipine, elidipine, felodipine, and the likeThe composition comprises a pharmaceutically acceptable carrier and a pharmaceutically acceptable carrier, wherein the carrier is selected from the group consisting of dipine, isradipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, cinnarizine, flunarizine, lidofloxacin, lomerizine, bencyclane, etaphenone, pantofalong, perhexiline, and mixtures thereof.

In some embodiments, the compounds of the present disclosure may be co-formulated or co-administered with opioid antagonists according to international patent application publication No. WO 03/084520, such as naltrexone, naloxone, nalmefene, nalprofen, nalbuphine, naloxone azurine (naloxonexazine), methylnaltrexone, ketelcin (ketelczochracine), beninamine (norbinaltorphine), naltrexone, 6- β -naloxonol, 6- β -naltrexone, alvimopan, cyprohexidine (propromine), diproporphine, gemazocine, 5' -guanidinonatroindole, JDTic ((3R) -7-hydroxy-N- [ (2S) -1- [ (3R, 4R) -4- (3-hydroxyphenyl) -3, 4-dimethylpiperidin-1-yl ] -3-methylbutan-2-yl ] -1, 2, 3, 4-tetrahydroisoquinoline-3-carboxamide), levorphanol, naldedine (naldeedine), nalmexone, nalprofen dinicotinate, naloxonizone (naloxazone), nalogel (naloxegol), naloxonol, naloxonazine (naloxonazine), nalteben (naltben), oxirphan, quadazocine, semaphorin (samidochan), and mixtures thereof.

Since certain compounds of the present disclosure may act as prodrugs, they may be used for the same purpose as their parent compounds. In some embodiments, the compounds of the present disclosure are useful for treating, ameliorating, or preventing pain, including acute pain, chronic pain, neuropathic pain, inflammatory pain, and surgical pain. In another embodiment, the compounds of the present disclosure are useful for treating, ameliorating, or preventing opioid-induced adverse pharmacodynamic responses.

The compounds of the present disclosure are useful for treating or preventing acute pain, chronic pain (including but not limited to neuropathic pain, post-operative pain, and inflammatory pain), or surgical pain. Examples of pain that can be treated or prevented using the compounds of the present invention include, but are not limited to, cancer pain, neuropathic pain, labor pain, myocardial infarction pain, pancreatic pain, angina, post-operative pain, headache, muscle pain, joint pain, and pain associated with periodontal disease (including gingivitis and periodontitis).

Acute pain includes, but is not limited to, perioperative pain, post-operative pain, post-traumatic pain, acute disease-related pain, and pain associated with diagnostic procedures, orthopedic procedures, and myocardial infarction. Acute pain in a perioperative setting includes pain caused by a pre-existing disease, a surgical procedure (e.g., associated drainage, thoracic, or nasogastric tube), or a complication or combination of disease-related and procedure-related sources.

Chronic pain includes, but is not limited to, inflammatory pain, post-operative pain, cancer pain, osteoarthritis pain associated with metastatic cancer, trigeminal neuralgia, acute herpetic and post-herpetic neuralgia, diabetic neuropathy, causalgia, brachial plexus avulsion, occipital neuralgia, reflex sympathetic dystrophy, fibromyalgia, gout, phantom limb pain, burn pain, and other forms of neuralgia, neuropathic and idiopathic pain syndromes.

The compounds of the present disclosure are useful for treating or preventing pain associated with inflammation or associated with an inflammatory disease in a patient. Such pain may occur where body tissues are inflamed (either as a local inflammatory response or as a systemic inflammation). For example, the compounds of the present disclosure are useful for treating or preventing pain associated with inflammatory diseases, including but not limited to organ transplant rejection; reoxygenation injury from organ transplantation (including but not limited to heart, lung, liver or kidney transplantation) (see Grupp et al, J. mol, Cell Cardiol.31: 297-303 (1999)); chronic inflammatory diseases of the joints including arthritis, rheumatoid arthritis, osteoarthritis and bone diseases associated with increased bone resorption; inflammatory bowel diseases, such as ileitis, ulcerative colitis, Barrett's syndrome, and crohn's disease; inflammatory lung diseases such as asthma, adult respiratory distress syndrome, and chronic obstructive airways disease; inflammatory diseases of the eye including corneal dystrophy, trachoma, onchocerciasis, uveitis, sympathetic ophthalmia, and endophthalmitis; chronic inflammatory diseases of the gums including gingivitis and periodontitis; tuberculosis; leprosy; inflammatory diseases of the kidney, including uremic complications, glomerulonephritis and renal disease; inflammatory diseases of the skin including sclerodermatitis, psoriasis and eczema; inflammatory diseases of the central nervous system, including chronic demyelinating diseases of the nervous system, multiple sclerosis, aids-related neurodegeneration and alzheimer's disease, infectious meningitis, encephalomyelitis, parkinson's disease, huntington's disease, amyotrophic lateral sclerosis and viral or autoimmune encephalitis; autoimmune diseases, including type I and type II diabetes; diabetic complications, including, but not limited to, diabetic cataracts, glaucoma, retinopathy, nephropathy (such as microalbuminuria and progressive diabetic nephropathy), gangrene of the foot, atherosclerotic coronary artery disease, peripheral arterial disease, nonketotic hyperglycemic-hyperosmolar coma, foot ulcers, joint problems, and skin or mucosal complications (such as infection, shin spot, candida infection, or diabetic lipogenic necrosis), immune complex vasculitis, and Systemic Lupus Erythematosus (SLE); inflammatory diseases of the heart, such as cardiomyopathy, ischemic heart disease hypercholesterolemia, and atherosclerosis; and various other diseases that may have significant inflammatory components, including preeclampsia, chronic liver failure, brain and spinal cord trauma, and cancer. The compounds of the present disclosure may also be used to treat or prevent pain associated with inflammatory diseases (which may be, for example, systemic inflammation of the body), such as gram-positive or gram-negative shock, hemorrhagic or anaphylactic shock, or shock induced by cancer chemotherapy in response to proinflammatory cytokines, such as shock associated with proinflammatory cytokines. Such shock can be induced, for example, by chemotherapeutic agents administered as a cancer treatment.

The compounds of the present disclosure are useful for treating or preventing pain associated with nerve injury (i.e., neuropathic pain). Chronic neuropathic pain is a heterogeneous disease state of unknown etiology. In chronic pain, pain can be mediated by a variety of mechanisms. This type of pain is generally caused by damage to peripheral or central nervous tissue. Syndromes include pain associated with spinal cord injury, multiple sclerosis, post-herpetic neuralgia, trigeminal neuralgia, phantom pain, causalgia, and reflex sympathetic dystrophy and back pain. Chronic pain differs from acute pain in that chronic neuropathic pain patients have abnormal pain sensations, which can be described as spontaneous pain, persistent superficial burning, and/or deep aching pain. Pain can be induced by hot, cold and mechanical hyperalgesia or, cold or mechanical allodynia.

Chronic neuropathic pain can be caused by injury or infection of peripheral sensory nerves. It includes, but is not limited to, pain from peripheral nerve trauma, herpes virus infection, diabetes, burning pain, plexus avulsion, neuroma, amputation and vasculitis. Neuropathic pain can also be caused by nerve damage due to chronic alcoholism, human immunodeficiency virus infection, hypothyroidism, uremia, or vitamin deficiency. Stroke (spinal cord or brain) and spinal cord injury can also induce neuropathic pain. Cancer-related neuropathic pain results from tumor growth pressing against adjacent nerves, brain or spinal cord. In addition, cancer treatments (including chemotherapy and radiation therapy) can cause nerve damage. Neuropathic pain includes, but is not limited to, pain caused by nerve injury, such as, for example, pain suffered by a diabetic patient.

The compounds of the present disclosure are useful for treating or preventing pain associated with migraine headaches including, but not limited to, migraine without aura ("common migraine"), migraine ("classical migraine"), migraine without cephalic, basilar migraine, familial hemiplegic migraine, migraine cerebral infarction, and migraine with prolonged aura.

In some embodiments, the compounds of the present disclosure are useful as antitussives and for treating or ameliorating dyspnea, diarrhea, and dysentery.

In each of the above mentioned cases, the methods of the present invention entail administering to a mammal in need of such treatment an effective amount of a compound of any one of formulas I to VI, or a pharmaceutically acceptable salt or solvate thereof, or a mixture thereof.

In some embodiments, compounds of the present disclosure are tested for μ, κ, or ORL-1 opioid receptor binding activity and their functional profile at the μ, κ, or ORL-1 opioid receptor by the following in vitro binding assay.

In vitro assay protocol

μ opioid receptor binding assay procedure: radioligand dose-displacement binding assays for mu opioid receptors can use 500. mu.l binding buffer (10mM MgCl) in a final volume ₂0.3nM [ 2 ] in 1mM EDTA, 5% DMSO, 50mM HEPES, pH7.4)³H]Diproporphine (Perkin Elmer, Shelton, CT) with 5mg membrane protein/well. The reaction is carried out in the absence or presence of increasing concentrations of unlabeled naloxone. All reactions were performed in 96 deep-well polypropylene plates for 2 hours at room temperature. The binding reaction was terminated by: rapid filtration was performed using a 96-well tissue harvester (Perkin Elmer, Shelton, CT) on 96-well Unifilter GF/C filter plates (Perkin Elmer, Shelton, CT) pre-soaked in 0.5% polyethyleneimine followed by 3 filter washes with 500. mu.l ice-cold binding buffer. The filter plates were subsequently dried at 50 ℃ for 2-3 hours. Betacint scintillation cocktail (Perkin Elmer, Shelton, CT) was added (50. mu.l/well) and plates were counted at 1 min/well using a Packard Top-Count. Using GraphPad PRISM^TMData were analyzed by a single-point competition curve fitting function in version 3.0 or higher (San Diego, Calif.) or an internal single-point competition curve fitting function. Data are expressed as mean ± s.e.m. The results are expressed as the inhibition constant K_iValue (concentration of compound that produces half-maximal inhibition).

μ opioid receptor functional assay procedure: using a newly thawed [ mu ] receptor membrane ³⁵S]GTP γ S function assays, membranes prepared internally from cell lines expressing recombinant μ opioid receptors in HEK-293, CHO or U-2 OS cell backgrounds or purchased from commercial sources (Perkin Elmer, Shelton, CT; or DiscovRx, Fremont, CA). By adding the following reagents sequentially to the ice binding buffer (100mM NaCl, 10mM MgCl)₂20mM HEPES, pH 7.4) to prepare the assay reaction (indicating final concentration): membrane protein (0.026mg/mL), saponin (10mg/mL), GDP (3mM) and [ alpha ], [ beta³⁵S]GTP γ S (0.20 nM; Perkin Elmer, Shelton, CT). The prepared membrane solution (190. mu.l/well) was transferred to96 shallow well polypropylene plates containing 10. mu.l of agonist [ D-Ala ] prepared in dimethyl sulfoxide (DMSO)²N-methyl-Phe⁴Gly-ol⁵]-20 x concentrated stock of enkephalin (DAMGO). The plates were incubated at about 25 ℃ for 30 minutes with shaking. The reaction was terminated by: rapid filtration on 96-well Unifilter GF/B filter plates (Perkin Elmer, Shelton, CT) using a 96-well tissue harvester (Perkin Elmer, Shelton, CT) followed by 200. mu.l ice-cold wash buffer (10mM NaH)₂PO₄，10mM Na₂HPO₄pH 7.4) were subjected to 3 filtration washes. The filter plates were subsequently dried at 50 ℃ for 2-3 hours. Betacint scintillation cocktail (Perkin Elmer, Shelton, CT) was added (50. mu.l/well) and plates were counted at 1 min/well using a Packard Top-Count. Data were analyzed using a sigmoidal dose response curve fitting function in GraphPad PRISM version 3.0 or an internal nonlinear sigmoidal dose response curve fitting function. Data are expressed as mean ± s.e.m. The results of the functional assay are expressed as EC ₅₀Value (effective concentration of compound that elicits 50% of maximal response).

The method can also be carried out using a freshly thawed [ mu ] receptor membrane prepared from a cell line expressing a recombinant [ mu ] opioid receptor in a CHO-K1 cell background³⁵S]And (4) measuring the function of GTP gamma S.

Kappa opioid receptor binding assay procedure: by running in ice-cold hypotonic buffer (2.5mM MgCl)₂50mM HEPES, pH 7.4) (10mL/10cm dish) to prepare membranes from HEK-293, CHO or U-2OS cells expressing recombinant human kappa opioid receptor (kappa), followed by homogenization with a tissue grinder/Teflon pestle. Membranes from cell lines that naturally express kappa opioid receptors may also be used. The membranes were harvested by centrifugation at 30,000x g for 15 minutes at 4 ℃ and the pellet resuspended in hypotonic buffer to a final concentration of 1-3 mg/mL. Protein concentration was determined using BioRad protein assay reagents with bovine serum albumin as standard. Aliquots of the kappa receptor membranes were stored at-80 ℃.

The radioligand dose-displacement assay can use 0.4nM [ mu ] m in a final volume of 200. mu.l of binding buffer (5% DMSO, 50mM Trizma base, pH 7.4)³H]-U69593(GE Healthcare, Piscataway, NJ; 40Ci/mmole) with 15. mu.g of membrane protein (recombinant kappa opioid receptor expressed in HEK293 cells; prepared internally). Non-specific binding was determined in the presence of 10. mu.M unlabeled naloxone or U69,593. All reactions were carried out in 96-well polypropylene plates at a temperature of about 25 ℃ for 1 hour. The binding reaction was stopped by rapid filtration on 96-well unifilter gf/C filter plates (Perkin Elmer, Shelton, CT) pre-soaked in 0.5% polyethyleneimine (Sigma). Collection was performed using a 96-well tissue harvester (Perkin Elmer, Shelton, CT) followed by five filter washes with 200. mu.l ice-cold binding buffer. The filter plates were subsequently dried at 50 ℃ for 1-2 hours. Add 50. mu.l/well scintillation cocktail (Perkin Elmer, Shelton, CT) and Count plates at 1 min/well in a Packard Top-Count. Using GraphPad PRISM ^TMData were analyzed by a single-point competition curve fitting function in version 3.0 or higher (San Diego, Calif.) or an internal single-point competition curve fitting function. Data are expressed as mean ± s.e.m. The results are expressed as the inhibition constant K_iValue (concentration of compound that produces half-maximal inhibition).

Kappa opioid receptor functional assay procedure: the function [ 2 ] can be performed as follows³⁵S]GTP γ S binding assay. By mixing kappa membrane protein (internal) at a final concentration of 0.026. mu.g/. mu.l, 10. mu.g/mL saponin, 3. mu.M GDP and 0.20nM³⁵S]GTP γ S was added to the ice binding buffer (100mM NaCl, 10mM MgCl) in sequence₂20mM HEPES, pH7.4) was prepared. The prepared membrane solution (190. mu.l/well) was transferred to 96 shallow well polypropylene plates containing 10. mu.l of 20 × concentrated stock of agonist prepared in DMSO. The plates were incubated at a temperature of about 25 ℃ for 30 minutes with shaking. The reaction was terminated by: using a 96-well tissue harvester (Packard), rapid filtration was performed on 96-well Unifilter GF/B filter plates (Perkin Elmer, Shelton, CT) followed by 200. mu.l of ice-cold binding buffer (10mM NaH)₂PO₄，10mM Na₂HPO₄pH7.4) was subjected to 3 filtration washes. The filter plates were subsequently dried at 50 ℃ for 2-3 hours. Add 50. mu.l/well scintillation cocktail (Perkin Elmer, Shelton, CT) and add to the mixture in a Packard Top-Count Plates were counted at 1 minute/well. Using GraphPad PRISM^TMData were analyzed by a single-point competition curve fitting function in version 3.0 or higher (San Diego, Calif.) or an internal single-point competition curve fitting function. Data are expressed as mean ± s.e.m. The results of the functional assay are expressed as EC₅₀Value (effective concentration of compound that elicits 50% of maximal response).

Opioid receptor binding assay procedure: the opioid receptor binding assay procedure was performed as follows. Radioligand dose-displacement assays can be performed using 500. mu.l binding buffer (5mM MgCl. sub.₂0.3nM [3 ] in 5% DMSO, 50mM Trizma base, pH 7.4)^H]Naltrendole (Perkin Elmer, Shelton, CT; 33.0Ci/mmole) with 5. mu.g of membrane protein (Perkin Elmer, Shelton, CT). Non-specific binding was determined in the presence of 25 μ M unlabeled naloxone. All reactions were carried out in 96 deep well polypropylene plates at a temperature of about 25 ℃ for 1 hour. The binding reaction was stopped by rapid filtration on 96-well Unifilter GF/C filter plates (Perkin Elmer, Shelton, CT) pre-soaked in 0.5% polyethyleneimine (Sigma). Collection was performed using a 96-well tissue harvester (Perkin Elmer, Shelton, CT) followed by five filter washes with 500. mu.l ice-cold binding buffer. The filter plates were subsequently dried at 50 ℃ for 1-2 hours. Add 50. mu.l/well scintillation cocktail (Perkin Elmer, Shelton, CT) and Count plates at 1 min/well in a Packard Top-Count. Using GraphPad PRISM ^TMData were analyzed by a single-point competition curve fitting function in version 3.0 or higher (San Diego, Calif.) or an internal single-point competition curve fitting function. Data are expressed as mean ± s.e.m. The results are expressed as the inhibition constant K_iValue (concentration of compound that produces half-maximal inhibition).

Opioid receptor function assay procedure: the function [ 2 ] can be performed as follows³⁵S]GTP γ S binding assay. By mixing a membrane protein (Perkin Elmer, Shelton, CT) at a final concentration of 0.026. mu.g/. mu.l, 10. mu.g/mL saponin, 3. mu.M GDP and 0.20nM [, ]³⁵S]GTP γ S was added to the ice binding buffer (100 mM NaCl, 10mM MgCl) in sequence₂20mM HEPES, pH7.4) was added to the aqueous solution. Will prepareThe membrane solution (190. mu.l/well) was transferred to 96 shallow well polypropylene plates containing 10. mu.l of 20 Xconcentrated stock of agonist prepared in DMSO. The plates were incubated at a temperature of about 25 ℃ for 30 minutes with shaking. The reaction was terminated by: using a 96-well tissue harvester (Packard), rapid filtration was performed on 96-well Unifilter GF/B filter plates (Perkin Elmer, Shelton, CT) followed by 200. mu.l of ice-cold binding buffer (10mM NaH)₂PO₄，10mM Na₂HPO₄pH7.4) were subjected to 3 filtration washes. The filter plates were subsequently dried at 50 ℃ for 1-2 hours. Add 50. mu.l/well scintillation cocktail (Perkin Elmer, Shelton, CT) and count plates at 1 min/well in a Packard Top-count. Using GraphPad PRISM ^TMData were analyzed by a single-point competition curve fitting function in version 3.0 or higher (San Diego, Calif.) or an internal single-point competition curve fitting function. Data are expressed as mean ± s.e.m. The results of the functional assay are expressed as EC₅₀Value (effective concentration of compound that elicits 50% of maximal response).

ORL-1 receptor binding assay procedure: can be administered in ice-cold hypotonic buffer (2.5mM MgCl)₂50mM HEPES, pH 7.4) (10ml/10cm dish) to prepare membranes (Perkin Elmer, Shelton, CT) from recombinant HEK-293 cells expressing human opioid receptor-like receptor (ORL-1) followed by homogenization with a tissue grinder/Teflon pestle. The membranes were harvested by centrifugation at 30,000x g for 15 minutes at 4 ℃ and the pellet resuspended in hypotonic buffer to a final concentration of 1-3 mg/ml. Protein concentration was determined using BioRad protein assay reagents with bovine serum albumin as standard. Aliquots of the ORL-1 receptor membrane were stored at-80 ℃.

Radioligand binding assays (screening and dose replacement) used 500. mu.l binding buffer (10mM MgCl. sub.₂0.1nM [ 2 ] in 1mM EDTA, 5% DMSO, 50mM HEPES, pH 7.4)³H]Nociceptin (PerkinElmer, Shelton, CT; 87.7Ci/mmole) with 12. mu.g of membrane protein. Non-specific binding was determined in the presence of 10nM unlabeled nociceptin (American peptide Company). All reactions were performed in 96 deep-well polypropylene plates for 1 hour at room temperature. Through the process is 0.5 percent The binding reaction was stopped by rapid filtration on 96-well Unifilter GF/C filter plates (Perkinelmer, Shelton, CT) pre-soaked in polyethyleneimine (Sigma). Collection was performed using a 96-well tissue harvester (Perkin Elmer, Shelton, CT), followed by three filter washes with 500. mu.l ice-cold binding buffer. The filter plates were subsequently dried at 50 ℃ for 2-3 hours. Add 50. mu.l/well scintillation cocktail (Perkin Elmer, Shelton, CT) and Count plates at 1 min/well in a Packardtop-Count. Data from screening and dose replacement experiments were performed using Microsoft Excel and GraphPad PRISM, respectively^TMThe curve fitting function in version 3.0 or higher or the internal single-site competition curve fitting function. Data are expressed as mean ± s.e.m. The results are expressed as the inhibition constant K_iValue (concentration of compound that produces half-maximal inhibition).

ORL-1 receptor function assay procedure: can be administered in ice-cold hypotonic buffer (2.5mM MgCl)₂Membranes (Perkin Elmer, Shelton, CT) from recombinant HEK-293 cells expressing human opioid receptor-like (ORL-1) were prepared by lysing the cells in 50mM HEPES, pH 7.4) (10ml/10cm dish) and subsequent homogenization with a tissue grinder/Teflon pestle. The membranes were harvested by centrifugation at 30,000x g for 15 minutes at 4 ℃ and the pellet resuspended in hypotonic buffer to a final concentration of 1-3 mg/ml. Protein concentration was determined using BioRad protein assay reagents with bovine serum albumin as standard. Aliquots of the ORL-1 receptor membrane were stored at-80 ℃.

The function [ 2 ] is performed as follows³⁵S]GTP γ S binding assay. By mixing ORL-1 membrane protein at a final concentration of 0.026. mu.g/. mu.l, saponin at 10. mu.g/ml, GDP at 3. mu.M and 2.20 nM³⁵S]GTP γ S was added to ice binding buffer (100mM NaCl, 10mM MgCl)₂20mM HEPES, pH 7.4) was added to the resulting solution to prepare an ORL-1 membrane solution. The prepared membrane solution (190. mu.l/well) was transferred to 96 shallow well polypropylene plates containing 10. mu.l of 20 Xconcentrated stock of agonist/nociceptin prepared in DMSO. Plates were incubated at room temperature for 30 minutes with shaking. The reaction was terminated by: rapid filtration on 96-well Unifilter GF/B filter plates (Perkin Elmer, Shelton, CT) using a 96-well tissue harvester (Packard), followed by 200. mu.l filtrationl Ice-cold binding buffer (10mM NaH)₂PO₄，10mM Na₂HPO₄pH 7.4) were subjected to 3 filtration washes. The filter plates were subsequently dried at 50 ℃ for 2-3 hours. Add 50. mu.l/well scintillation cocktail (Perkin Elmer, Shelton, CT) and Count plates at 1 min/well in a Packard Top-Count. Data were analyzed using a sigmoidal dose response curve fitting function in GraphPad PRISM version 3.0 or higher or an internal nonlinear sigmoidal dose response curve fitting function. The results of the functional assay are expressed as EC₅₀Value (effective concentration of compound that elicits 50% of maximal response).

In vivo pharmacology

Brain distribution: the in vivo distribution of the compounds of the present disclosure in the brain after oral administration can be tested using, for example, the following test. Sprague Dawley rats were orally administered 10mg/kg of the test compound. Dosing solution was in 25% 2-hydroxypropyl β -cyclodextrin (HPBCD) and dosing volume was 5 mL/kg. One hour after administration, the highest possible volume of blood was withdrawn by cardiac puncture. Plasma was separated from whole blood by centrifugation and submitted for analysis. After bleeding, whole brains were collected, briefly rinsed in cold saline, and then snap frozen in liquid nitrogen. Both plasma and brain samples were stored at-70 ℃ prior to analysis.

To analyze plasma samples, calibration curves were prepared by spiking known amounts of analyte into commercially available control rat plasma. To 200. mu.l aliquots of the standard and study sample, 800. mu.l of an aqueous solution of the internal standard (oxycodone) was added and the reaction mixture was incubated at C according to the following procedure₁₈Extraction on solid phase cartridge (96 well format, 3M). The cartridge was activated by sequential application of 500 μ l methanol, 500 μ l water. The sample was then applied and the cartridge was washed with 500 μ l water and then eluted sequentially with 2x500 μ l methanol with 1% formic acid, 2x500 μ l methanol with 2% ammonia. After evaporation and reconstitution, the samples were analyzed by LC/MS/MS. To analyze brain samples, study samples and control brains were homogenized with water at a 1: 10 weight ratio per volume. A calibration curve was prepared by spiking a known amount of analyte into a control brain homogenate. To a 500. mu.L aliquot of the standard and study sample was added 500. mu.l of an aqueous solution of the internal standard (oxycodone) and According to the procedure described earlier for plasma samples at C₁₈Extraction on solid phase cartridge (96 well format, 3M). After evaporation and reconstitution, the samples were analyzed by LC/MS/MS.

Using procedures known in the art in Zorbax Extended C₁₈The analytes and internal standards were chromatographed on a column (4.6x150mm, 3.5 micron particle size) under water-acetonitrile gradient conditions (specific gradient for each analyte). The effluent was analyzed by MS/MS. The analyte is registered as a "daughter" ion of an "analyte" molecular ion on the second quadrupole of the instrument. MS/MS conditions were optimized for each analyte to achieve maximum selectivity and sensitivity.

The concentration of the unknown sample is calculated based on the parameters of the corresponding calibration curve. The brain concentration expressed as "ng/g tissue" is obtained by multiplying the corresponding homogenate concentration by a factor of 10 (dilution factor during the homogenization step). Brain-blood ratios were calculated as the ratio of the corresponding brain (ng/g) concentration to plasma (ng/mL) concentration for each animal and mean and standard deviation were calculated for the triplicate groups.

Anti-nociceptive activity studies in mice: can be found in, for example, Hunskaar, s., o.b.faster and k.hole, j.neurosci.methods 14: 69-76(1985) the compounds of the invention were tested for antinociceptive activity in the formalin model described in section (A). Male Swiss Webster NIH mice (20-30 g; Harlan, san Diego, Calif.) were used in all experiments. Food was withdrawn on the day of the experiment. Mice were placed in plexiglass jars for at least 1 hour to acclimate to the environment. After the adaptation period, mice were weighed and given either the target compound or an appropriate volume of vehicle (10% Tween-80) orally administered in vehicle. Formalin (20 μ l saline containing 5% formaldehyde solution) was injected into the dorsal surface of the right hind paw of the mouse 30 minutes after oral administration. Mice were transferred to plexiglass jars and the amount of time it took to lick or bite the injected paw was monitored. The lick and bite cycle was recorded at 5 minute intervals within 1 hour after formalin injection. All experiments were performed in a blind manner during the light cycle. The early measurement of formalin response was between 0 and 5 minutes licking/biting and the later was measured from 15 to 50 minutes. Differences between vehicle and drug-treated groups were analyzed by one-way analysis of variance (ANOVA). The p value ≦ 0.05 was considered significant. Compounds with activity that block the acute and second phases of formalin-induced paw licking activity are considered to be effective against acute and chronic pain.

In vivo pain assay using rats as test animals

Test animals: the experiments began with rats weighing between 200-260 g. Rats were housed in groups and had free access to food and water all the time until oral administration of a compound of the present disclosure, at which time food was removed approximately 16 hours prior to dosing. A control group was used as a comparison to rats treated with a compound of the present disclosure. The vehicle for the compound of the present disclosure was administered to the control group. The volume of vehicle administered to the control group was the same as the volume of vehicle and compound of the present disclosure administered to the test group.

Acute pain: to assess the effect of the compounds of the present disclosure in treating or preventing acute pain, a tail flick of the rat may be used. The rats were gently restrained by hand and a point 5cm from the tip of the tail was exposed to a focused beam of radiant heat using a tail flick device (model 7360, commercially available from Ugo Basile, italy). The tail flick latency is defined as the interval between the onset of thermal stimulation and the tail flick. Animals that did not respond within 20 seconds were removed from the tail flick device and assigned a withdrawal latency of 20 seconds. Tail-flick latencies were measured immediately upon administration of the compounds of the present disclosure (before treatment) and 1, 3, and 5 hours after administration of the compounds of the present disclosure. The data are expressed as tail flick latencies and the percentage of the maximum possible effect (% MPE), i.e. 20 seconds, is calculated as follows:

Rat tail flick tests are described in f.e.d' amuur et al, "a Method for Determining Loss of pain sensing," j.pharmacol. exp. ther. 72: 74-79 (1941).

To assess the effect of the compounds of the present disclosure in treating or preventing acute pain, a rat hotplate test may also be used. Rats were tested using a hotplate apparatus consisting of a transparent plexiglas cylinder with a heated metal floor maintained at a temperature of 48-52 ℃ (model 7280, commercially available from Ugo Basile, italy). The rats were placed in the cylinder on a hotplate apparatus for a maximum duration of 30 seconds, or until they exhibited pain response behavior (behavioral endpoint), at which time the rats were removed from the hotplate and the response latency was recorded. Hotplate latency was measured immediately upon administration of the compounds of the invention (before treatment) and 1, 3 and 5 hours after administration of the compounds of the invention. Pain response behavioral endpoints are defined as any one of: 1) paw withdrawal, continuous lifting or shaking or licking; 2) alternately lifting feet; 3) escape or attempted escape from the test device; or 4) sounding. Data are expressed as response latencies and the maximum percent possible effect is calculated as described above for the tail-flick test. Hot plate testing is described in g.woolfe and a.d.macdonald, j.pharmacol.exp.ther.80: 300-307 (1944).

Inflammatory pain: to assess the effect of the compounds of the present disclosure in treating or preventing inflammatory pain, a freund's incomplete adjuvant ("FCA") model of inflammatory pain may be used. FCA-induced Inflammation of the rat hind paw is associated with the appearance of persistent inflammatory mechanical Hyperalgesia and provides a reliable predictor of the anti-hyperalgesic effect of clinically available analgesic drugs (L.Bartho et al, "infection of Capsaicin-sensitive nerves in Hyperalgesia and enhanced optioceptic in Inflammation," naunon-schmiedberg's Archives of Pharmacol.342: 666-. 50 μ L of 50% FCA intraplantar injection was applied to the left hind paw of each animal. Animals were assessed for response to noxious mechanical stimuli by determining PWT before FCA injection (baseline) and 24 hours after injection, as described below. Followed by administering to the rat a single injection of 1, 3 or 10mg/kg of a compound of the invention; 30mg/kg of a control drug selected from celecoxib, indomethacin or naproxen; or a carrier. Responses to noxious mechanical stimuli were determined at 1, 3, 5 and 24 hours after administration. The percent recovery of hyperalgesia in each animal was defined as:

[ (post-administration PWT) - (pre-administration PWT) ]

Recovery% — x 100

[ (Baseline PWT) - (PWT before administration) ]

Neuropathic pain: to assess the effect of the compounds of the present disclosure in treating or preventing neuropathic pain, a Seltzer model or Chung model may be used.

In the Seltzer Model, a local Sciatic Nerve ligation Model of Neuropathic Pain was used to generate Neuropathic hyperalgesia in Rats (Z. Seltzer et al, "A Novel Bei visual Model of Neuropathic Pain disorders Produced in rays by Partial scientific Nerve, in" Pain 43: 205-. In isoflurane/O₂Local ligation of the left sciatic nerve was performed under inhalation anesthesia. After induction of anesthesia, the left thigh of the rat was shaved and the sciatic nerve was exposed at a high level of the large leg through a small incision and the surrounding connective tissue was carefully cleared in the vicinity of the trochanteric membrane just distal to the point where the posterior biceps semitendinosus nerve bifurcates the common sciatic nerve. The 7-0 suture thread was inserted into the nerve with an 3/8 curved reverse cut mini-needle and tightly ligated such that the dorsal part 1/3 to 1/2 of the nerve thickness remained within the ligature. The wound was closed with a single muscle suture (4-0 nylon (Vicryl)) and vetbond tissue glue. After surgery, the wound area is sprayed with antibiotic powder. Sham-treated rats underwent the same surgical procedure except that the sciatic nerve was not manipulated. After surgery, animals were weighed and placed on a warm pad until they recovered from anesthesia. The animals were then returned to their home cages until the behavioral testing began. The response of animals to noxious mechanical stimuli is assessed by measuring PWT prior to surgery (baseline), followed immediately upon drug administration and 1, 3 and 5 hours after drug administration, as described below. The percent recovery of neuropathic hyperalgesia is defined as:

In the Chung model, the spinal nerve ligation model of neuropathic pain was used to generate mechanical hyperalgesia, thermal hyperalgesia and tactile allodynia in rats. In isoflurane/O₂Surgery was performed under inhalation anesthesia. After induction of anesthesia, a 3cm incision was made and placed at L₄-S₂Horizontally shift the left paraspinal muscleIs separated from the spinous process. Carefully remove L with a pair of small rongeurs₆Transverse process to visually identify L₄-L₆The spinal nerve. Separate left side L₅(or L)₅And L₆) Spinal nerves were tightly ligated with silk threads. Complete hemostasis is confirmed and the wound is closed using non-absorbable sutures (e.g., nylon sutures or stainless steel staples). Sham-treated rats underwent the same surgical procedure except that the spinal nerves were not manipulated. Animals were weighed post-operatively, injected subcutaneously (s.c.) with saline or ringer's lactate, and the wound area was sprayed with antibiotic powder and maintained on a warm pad until they recovered from anesthesia. The animals were then returned to their home cages until the behavioral testing began. As described below, the response of animals to noxious mechanical stimuli is assessed by measuring PWT prior to surgery (baseline), immediately following administration of the compounds of the invention, and 1, 3, and 5 hours after administration of the compounds of the invention. Animals can also be assessed for response to noxious thermal stimuli or tactile allodynia, as described below. Chung models of neuropathic Pain are described in s.h. kim, "An Experimental Model for Experimental neuropathic Produced by segmented Spinal neutral Pain activation in the rat," Pain 50 (3): 355-363 (1992).

Response to mechanical stimuli as an assessment of mechanical hyperalgesia: mechanical hyperalgesia can be assessed using a paw pressure assay. For this determination, the hindpaw withdrawal threshold (PWT) for noxious mechanical stimuli was determined using a tenderness apparatus (model 7200, commercially available from UgoBasile, italy) as described in the following documents: stein, "Universal information of the Hindpaw in rates as a Model of Projoined NoxiousStulation: alternans in bhavior and Nociceptive Thresholds, "pharmacol, biochem, and bhavior 31: 451-455(1988). The rats were gently restrained, their hind paws placed on a small circular platform, and punctate pressure was applied to the dorsal surface of the hind paws in a graduated fashion. The maximum weight applied to the hind paw was set at 250g and the endpoint was taken as the paw was fully retracted. At each time point, each rat was assayed for PWT-times and tested either only for affected (ipsilateral; ipsilateral to injury) hind paws, or for both ipsilateral and contralateral (uninjured; opposite injury) hind paws.

Response to thermal stimulus as an assessment of thermal hyperalgesia: thermal hyperalgesia can be assessed using the plantar test. For this test, plantar testing equipment (commercially available from Ugo Basile, Italy) was used, in accordance with the protocol as described by K.Hargreaves et al, "A New and Sensitive Method for Measuring Thermal Noception in Cutaneous Hyperagesia," paper 32 (1): 77-88(1988), determining hindpaw withdrawal latency to noxious thermal stimuli applied to the plantar surface of the hindpaw. The maximum exposure time was set at 32 seconds to avoid tissue damage, and paw withdrawal from any direction of the heat source was considered the endpoint. Three latencies were measured at each time point and averaged. Only affected (ipsilateral) paw was tested, or both ipsilateral and contralateral (intact) paw were tested.

Assessment of tactile allodynia: to assess tactile allodynia, rats were placed in a clear plexiglas compartment with a wire mesh floor and habituated for a period of at least 15 minutes. After habituation, a series of von Frey monofilaments were presented to the plantar surface of each rat's affected (ipsilateral) foot. The series of von Frey monofilaments consists of six monofilaments of increasing diameter, with the smallest diameter fiber appearing first. Five trials were run with each filament, with each trial being approximately 2 minutes apart. Each presentation lasted for a period of 4-8 seconds, or until nociceptive withdrawal behavior was observed. Flinching, paw withdrawal or licking of the paw are considered nociceptive behavioral responses.

Evaluation of respiratory depression: to assess respiratory depression, rats were prepared by implanting a femoral artery cannula from which blood samples were taken. Blood samples were taken 1, 3, 5 and 24 hours after treatment, prior to drug administration. Blood samples are processed using an arterial blood gas analyzer (e.g., IDEXX VetStat with breath/blood gas test cartridges). A comparable device is a standard tool for blood gas analysis (e.g., D.Torbati et al, Intensive Care Med. (26): 585-.

Evaluation of gastric motility: animals were treated with vehicle, reference compound or test article by oral gavage in a volume of 10 mL/kg. One hour after dosing, all animals were treated with a 10mL/kg volume of charcoal powder solution (5% non-activated charcoal powder in 1% carboxymethyl cellulose aqueous solution). Two hours after dosing (one hour after charcoal), animals were sacrificed by carbon dioxide inhalation or over-administration of isoflurane and passage of charcoal powder was identified. The stomach and small intestine were carefully removed and each was placed on a saline soaked absorbent surface. The distance between the pylorus and the furthest progression of charcoal powder was measured and compared to the distance between the pylorus and the ileocecal junction. Charcoal powder passage is expressed as a percentage of the length of the small intestine travelled.

The compositions of the present disclosure are prepared by a process comprising mixing a compound of the present disclosure with a pharmaceutically acceptable carrier or excipient. Mixing can be accomplished using known methods of mixing the compound (or derivative) and a pharmaceutically acceptable carrier or excipient. In one embodiment, the compounds of the present disclosure are present in the composition in an effective amount.

The disclosure also relates to a kit comprising a sterile container containing an effective amount of a compound of the disclosure and instructions for therapeutic use.

The following examples are illustrative of the compounds, compositions and methods of the present invention, but are not intended to be limiting. Appropriate modifications and adaptations of various conditions and parameters normally encountered in clinical therapy and which would be apparent to those skilled in the art in view of this disclosure are within the spirit and scope of the invention.

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